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HANDBOOK OF EPIGENETICS
 HANDBOOK OF
EPIGENETICS
The New Molecular and Medical
Genetics
THIRD EDITION

Edited by

TRYGVE O. TOLLEFSBOL
Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States; O’Neal Comprehensive Cancer Center,
University of Alabama at Birmingham, Birmingham, AL, United States; Integrative Center for Aging Research, University of Alabama at
Birmingham, Birmingham, AL, United States; Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL,
United States; Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, United States; University Wide
Microbiome Center, University of Alabama at Birmingham, Birmingham, AL, United States
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 Contents

List of contributors xiii 4. The Epigenetics of Noncoding RNA 55

RAVINDRESH CHHABRA

I Introduction 55
Overview Conclusions 67
Acknowledgments 67
References 68
1. Epigenetics Overview 3
TRYGVE O. TOLLEFSBOL 5. Prions and prion-like phenomena in
epigenetic inheritance 73
Introduction 3 PHILIPPE SILAR
Molecular Mechanisms of Epigenetics 3
Methods in Epigenetics 4 Structural Heredity 74
Model Organisms of Epigenetics 5 Amyloid Prions of Saccharomyces cerevisiae,
Factors Influencing Epigenetic Changes 5 Podospora anserina, and Other Organisms 74
Evolutionary Epigenetics 6 Cis Elements Important for Amyloid Prion Formation 76
Epigenetic Epidemiology 6 Genetic Control of Amyloid Prion Formation and
Epigenetics and Human Disease 7 Propagation 76
Epigenetic Therapy 7 Amyloid Prion Variants 77
The Future of Epigenetics 7 Self-Driven Assembly of Hsp60 Mitochondrial Chaperonin 77
Conclusion 8 Cytotaxis of Cilia and Other Complex Structures 78
References 8 Mixed Heredity: “Nonamyloid Prions” That Propagate by
Auto-activation 78
II Regulatory Inheritance
The Lactose Operon and Its Positive Feedback Loop
79
79
Molecular Mechanisms of Epigenetics Crippled Growth, A Self-sustained and Mitotically
Inheritable Signaling Pathway in the Filamentous Fungus
Podospora anserina 80
The White/Opaque Switch of Candida albicans,
2. Mechanisms of DNA Methylation and
An Epigenetic Switch at the Transcription Level 81
Demethylation During Mammalian Conclusion 82
Development 11 References 83
ZHENGZHOU YING AND TAIPING CHEN

Introduction 11 6. Higher-order Chromatin Organization in

DNA Methylation 12 Diseases, from Chromosomal Position Effect to
DNA Demethylation 17 Phenotype Variegation 89
Conclusions 20 FRÉDÉRIQUE MAGDINIER AND JÉRÔME D. ROBIN
Acknowledgments 21
References 22 Introduction 89
Chromosomal Position Effect in Human Pathologies 93
Telomeric Position Effect; Implication in Human Pathologies 98
3. Mechanisms of Histone Modifications 27 Conclusions 101
LUDOVICA VANZAN, ATHENA SKLIAS, MARIA BOSKOVIC, References 102
ZDENKO HERCEG, RABIH MURR AND DAVID M. SUTER

Introduction 27 7. Polycomb-group proteins and epigenetic

Main Histone Modifications 28 control of gene activity 111
Role of Aberrant Histone Modifications in Disease 45 PRASAD PETHE
Conclusions 45
References 46 Introduction 111

v
vi Contents

Polycomb Repressive Complexes 112 10. Techniques for Analyzing Genome-wide

Mechanism of Gene Regulation by Polycomb Expression of Non-coding RNA 163
Group Proteins 112
RENA ONOGUCHI-MIZUTANI, KENZUI TANIUE,
PcG-Mediated Control of Gene Expression in KENTARO KAWATA, TOSHIMICHI YAMADA AND
Stem Cells to Maintain Homeostasis 114 NOBUYOSHI AKIMITSU
PcG-mediated Control of Gene Expression in
Embryonic Stem Cells 116 Introduction 163
PcG-mediated Control of Gene Expression in cDNA Library Construction 164
Cancer Cells 117 Analysis of RNA-seq Data for ncRNAs 169
Conclusion and Future Perspective 118 Estimating the Transcription and
Acknowledgment 118 Degradation Rates of Non-Coding Transcripts 172
References 118 Conclusions 174
Dyrec-seq Protocol 175
Acknowledgments 177
III References 178
Methods in Epigenetics
11. Computational Epigenetics:
8. Methods for Analyzing DNA Cytosine The Competitive Endogenous RNAs Network
Modifications Genome-wide 123 Analysis 185
TIBOR A. RAUCH AND GERD P. PFEIFER LOO KEAT WEI

Introduction 123 Introduction 185

Methylated DNA Immunoprecipitation 124 Basic Principles of Competitive Endogenous RNAs 185
MBD Protein-based Affinity Pulldown 124 The Competitive Endogenous RNAs Network 186
Methylated-CpG Island Recovery Assay 125 Mathematical Models for Competitive Endogenous RNAs
Targeted Bisulfite Sequencing 125 Network Analysis 187
Infinium and EPIC Methylation Bead Chips 127 Comparison of Mathematical Models for Competitive
Whole Genome Bisulfite Sequencing 127 Endogenous RNAs Network Analysis 190
Other Sodium Bisulfite-based Approaches 128 Computational Epigenetic Approaches for Competitive
Enzymatic Methyl-sequencing and Pyrimidine Endogenous RNAs Network Analysis 190
Borane-based Methods 129 Conclusion 195
5-Hydroxymethylcytosine Mapping Methodologies 130 Acknowledgments 196
TET-assisted Bisulfite Sequencing 131 Conflict of Interest Statement 196
Oxidative Bisulfite Sequencing 131 References 196
APOBEC-coupled Epigenetic Sequencing 131
SMRT-seq and Nanopore Sequencing 131
Single Cell Whole Genome Methylation Analysis 132
Future Directions and Challenges 133 IV
Acknowledgments 133 Model Organisms of Epigenetics
References 133

9. Genome-wide Analyses of Histone 12. Epigenetic Mechanisms in Bacteria Bridge

Modifications in the Mammalian Genome 137 Physiology, Growth and Host Pathogen
Interactions 201
SHULAN TIAN, SUSAN L. SLAGER, ERIC W. KLEE AND
HUIHUANG YAN MARIA MIAH, MIHALY MEZEI AND SHIRAZ MUJTABA

Introduction 137 Introduction 201

Histone Modifications in Regulatory Regions 138 Protein Phosphorylation in Prokaryotes 201
High-throughput Assays for Mapping Histone DNA Methylation in Bacteria 204
Modifications 139 Protein Methylation 207
Genome-wide Mapping of Histone Modifications 145 Crosstalks Between Epigenetic Modifications 209
Catalog of Histone Modification Profiles 149 Conclusions and Future Perspectives 209
Variation of Histone Modifications 149 Summary 210
Conclusions and Perspectives 153 Protocols for Molecular Modeling 210
ChIP-seq Data Analysis Workflow 154 References 211
Acknowledgments 157 Further Reading 213
References 158
 Contents vii
13. Drosophila Epigenetics 215 DNA methylation during mammalian early embryo
AKANKSHA BHATNAGAR, ASHLEY M. KARNAY AND
development 291
FELICE ELEFANT Dynamic changes and function of histone modifications
in early embryo development 293
Introduction: Drosophila as a Model Organism in Epigenetic Summary 298
Research 216 References 299
Epigenetic Modification of Histone Proteins
Regulate Chromatin Packaging and Gene Control in
Drosophila 217
Position-Effect Variegation 220
17. Epigenetic Biomarkers 303
The Role of Epigenetics During Drosophila Development: XIAOTONG HU
Epigenetic Memory 223
Dosage Compensation 229 Introduction 303
The Epigenetic Language in Postmitotic Neurons Epigenetic biomarkers offer distinct advantages
Underlying Cognitive Function 232 over genetic biomarkers 304
Conclusion 238 Minimally invasive tissues are suitable for detecting
Protocol 238 epigenetic biomarkers 305
References 241 Field cancerization and epigenetic biomarkers 306
Potential DNA methylation biomarkers in cancer and
other diseases 307
14. Models of Mouse Epigenetic Inheritance: Potential m6A methylation biomarkers in cancer and
Classification, Mechanisms, and Experimental other diseases 308
Potential histone modification biomarkers in cancer and
Strategies 249
other diseases 309
COURTNEY W. HANNA Potential non-coding RNA biomarkers in diseases 310
Epigenetic biomarker detection methods in the clinic 313
Introduction 249
Challenges and future perspectives 316
Epigenetic Programming in Gametogenesis 250
References 317
Epigenetic Re-Programming During Embryogenesis 251
Metastable Epialleles 251
Genomic Imprinting 253
Conclusions 259 18. Transposable Elements Shaping the
Acknowledgments 259 Epigenome 323
References 259 KAREN GIMÉNEZ-ORENGA AND ELISA OLTRA

Introduction 323
15. Plant Epigenomics 263 Classification and structure of transposable elements 324
LEONARDO FURCI, JÉRÉMY BERTHELIER, OSCAR JUEZ, MATIN Transposable elements genomic annotation 328
MIRYEGANEH AND HIDETOSHI SAZE Epigenetic control of transposable elements 329
Factors influencing transposable elements epigenetics 334
Introduction 263
Influence of transposable elements on host epigenetics 335
Basic Mechanisms of Plant Epigenome Regulation 264
Concluding remarks 343
Epigenetic Phenomena in Plants 268
References 343
Epigenetic Regulation of Transposable Elements and
Interactions With Genes 269
Epigenetic Regulation of Stress Responses in Plants 271
Emerging Technologies for Epigenome Studies in Plants 276 19. Dietary and Metabolic Compounds
Future Perspectives 278 Affecting Covalent Histone Modifications 357
References 279 GARETH W. DAVISON

Introduction 357
V Metabolic and Dietary Control of Histone and
Transcriptional Dynamics 359
Factors Influencing Epigenetic Changes Regulation of Chromatin Dynamics 360
Histone Demethylation 362
Histone Acetylation 367
16. Dynamic Changes in Epigenetic Modifications Other Histone Modifications 373
During Mammalian Early Embryo Development 289 Concluding Perspectives 374
JIE YANG AND WEI JIANG Acknowledgments 375
References 375
Introduction 289 Further reading 380
viii Contents

20. Epigenetics, Stem Cells, Cellular Histone Acetylation and HATs 445
Differentiation, and Associated Neurological Histone Deacetylation and Histone Deacetylases 447
Histone Methylation 448
Disorders and Brain Cancer 381
Histone Modifications: Gene Expression 449
BHAIRAVI SRINAGESHWAR, GARY L. DUNBAR AND Manipulating Histone Modifications 450
JULIEN ROSSIGNOL
DNA Methylation and Long-term Memory 452
Introduction to Epigenetics 382 Histone Variant Exchange 456
Epigenetics and the Human Brain 383 Epitranscriptomics: RNA Epigenetics 457
Epigenetics and Glioblastoma 394 Summary 458
Epigenetic Changes in Glioma Stem Cells 394 Acknowledgments 458
Genes Involved in Glioblastoma 395 References 458
Stem Cell Transplantations in Glioblastoma 396
Neural Stem Cell Transplantation for GB 397
Conclusions 397
24. Transgenerational Epigenetics 465
References 398 JAMES P. CURLEY, RAHIA MASHOODH AND
FRANCES A. CHAMPAGNE

21. Epigenetic Regulation of Skeletal Muscle Introduction 465

Epigenetic Consequences of Prenatal Maternal Exposures 466
Regeneration 403
Postnatal Maternal Regulation of the Epigenome 468
RODOLFO DANIEL ÁVILA-AVILÉS, CLAUDIA NEGRÓN-LOMAS AND Paternal Influence on Offspring Development 469
J. MANUEL HERNÁNDEZ-HERNÁNDEZ
Transgenerational Effects of Parental Influence 469
Introduction 403 Germline-mediated Transgenerational Inheritance 470
Epigenetic Control in the Maintenance of Quiescence 404 Experience-dependent Epigenetic Inheritance 471
Epigenetic Control of the Activation and Proliferation Epigenetics, Plasticity, and Evolving Concepts of
of SCs 406 Inheritance 472
Epigenetic Control of SCs Differentiation 408 Summary 473
Small Molecules as a Therapeutic Alternative in the Acknowledgments 473
Epigenetic Control of Regeneration 410 References 473
Conclusion 412
Acknowledgments 413
References 413
25. DNA Methylation Clocks in Age-related
Disease 479
PETER D. FRANSQUET, JO WRIGGLESWORTH AND JOANNE RYAN
22. Epigenetics of X-chromosome Inactivation 419
CÍNTIA BARROS SANTOS-REBOUÇAS Aging 479
Epigenetic Clocks 480
Introduction 419 First Generation Epigenetic Clocks 480
Brief Historical Perspective of XCI 420 Second Generation Epigenetic Clocks 484
X-chromosome Evolution and the Incomplete Nature Epigenetic Clocks and Age-related Disease 485
of XCI 420 Epigenetic Clocks Without an Age-related Disease Focus 488
Imprinted and Random XCI 422 Can Epigenetic Age be Modified? 489
XCI Regulation and Main Epigenetic Steps 423 Summary 491
XCI Differences Between Mice and Humans 427 References 491
X-autosome Dosage Compensation 427
Methods for Exploring XCI Status 429
Physiological and Pathogenic XCI Skewing 429 VI
X-chromosome, Sex Bias and Diseases 432 Evolutionary Epigenetics
XCI Plasticity: Opportunities for Epigenetic Therapeutics 434
Concluding Remarks 434
Acknowledgments 434
References 436
26. Evolution of Epigenetic Mechanisms
in Plants: Insights from H3K4 and H3K27
Methyltransferases 499
23. Epigenetics of Memory Processes 443 J. ARMANDO CASAS-MOLLANO, ERICKA ZACARIAS AND
SRAVANI PULYA AND BALARAM GHOSH JULIANA ALMEIDA

Introduction 443 Introduction 499

Histone Posttranslational Modifications: Long-term Memory Histone Lysine Methylation 500
Regulation 444 Histone Lysine Methyltransferases in Plants 500
 Contents ix
Evolution of Plant Histone Lysine Methyltransferases Livestock Epigenetics Case Study 595
Methylating H3K4 502 Acknowledgment 598
Evolution of Plant Histone Lysine Methyltransferases References 599
Methylating H3K27 508
Perspectives 514
Acknowledgments 515 30. Nutritional Epigenetics and Fetal Metabolic
References 515 Programming 611
HO-SUN LEE

27. Evolution, Functions and Dynamics of Introduction 611

Epigenetic Mechanisms in Animals 521 Metabolic Sensing by Epigenetic Mechanisms 612
GÜNTER VOGT Impact of Prenatal Nutrition on Fetal Reprogramming 615
Maternal Diet and Metabolic Epigenome 616
Introduction 521 Summary and Perspectives 619
Evolution of Epigenetic Mechanisms in The Animal Acknowledgments 620
Kingdom 521 References 620
Features of Epigenetic Mechanisms and Role in Gene
Regulation 524
Dynamics of Epigenetic Marks During Development 526 31. Epigenetics of Drug Addiction 625
Generation of Phenotypic Variation in Populations by RYAN D. SHEPARD AND FERESHTEH S. NUGENT
Epigenetic Mechanisms 530
Relevance of Epigenetics for Animal Ecology 534 Introduction 625
Relevance of Epigenetics for Animal Evolution 538 What Is Addiction? 626
Conclusions and Perspectives 543 Dopamine and Reward Circuits 626
Summary 545 Synaptic Plasticity, Learning and Memory and
References 545 Addiction 628
Epigenetic Processes in Drug Addiction 630
Utilizing Epigenetic Targets for Diagnosis and Treatments to
28. Adaptive evolution and epigenetics 551 Combat Addiction and SUDs 632
ILKKA KRONHOLM Conclusion 634
Summary 634
Introduction 551 Acknowledgments 634
Epigenetic Variation 551 References 634
Modeling Evolution 552 Further Reading 637
Induced Epigenetic Changes 552
Spontaneous Epigenetic Variation 554
Modeling Spontaneous Epigenetic Variation 555 32. Environmental Influence on Epigenetics 639
Limits of Epigenetic Contributions to Adaptation 559 MARISOL RESENDIZ, DARRYL S. WATKINS,
Conclusions and Future Directions 560 NAIL CAN ÖZTÜRK AND FENG C. ZHOU
Acknowledgments 561
References 561 Introduction 639
The Extent (Timeline) of Environmental Influence 641
Exerting Environment 642
VII Mental or Physiological Environment 643
Hazardous Environmental Pollutants and Chemicals 650
Epigenetic Epidemiology Conclusion and Future Direction 658
Research case study [18] 660
References 663
29. Epigenetics of Livestock Health, Production,
and Breeding 569
EVELINE M. IBEAGHA-AWEMU AND HASAN KHATIB
33. Gut Microbiome Influence on Human
Epigenetics, Health, and Disease 669
Introduction 569 MARTIN M. WATSON, MARK VAN DER GIEZEN AND KJETIL SØREIDE
Development of Animal Breeding 570
Epigenetic Source of Phenotypic Variation in Livestock Introduction 669
Health and Production 571 Early Microbiome Exposure and Epigenetic Influence 673
Revisiting Animal Breeding Planning and Management: Human Gut Microflora 675
The Role of Epigenetic Mechanisms 587 Microbiome, Epigenetics, and Effect on Metabolism 675
Conclusion 595 Gut microbiota, Inflammation, and Colorectal
Summary 595 Carcinogenesis 677
x Contents

Pathogenic Infections and Cancer 677 Type 1 Diabetes Mellitus 724

Pathogenic Infections and Epigenetic Modifications 680 Systemic Sclerosis 725
Summary 683 Use of Epigenetic Modifications as Potential
References 683 Biomarkers 726
Use of Epigenetic Modifiers for Potential Diagnosis and
Therapy in Autoimmune Diseases 727
Summary 728
34. Population Pharmacoepigenomics 687 Multiomics and machine learning accurately predict
JACOB PEEDICAYIL clinical response to adalimumab and etanercept
therapy in patients with rheumatoid arthritis [203] [ex:
Introduction 687 Autoimmunity Epigenetics Case Study] 728
General Aspects of Population Pharmacoepigenomics 688 References 730
Population Variations of Epigenetic Patterns and
Population Pharmacoepigenomics 688
Human Epigenome Projects and Population
Pharmacoepigenomics 688 37. Epigenetics of Brain Disorders 737
Population Pharmacoepigenomics in Relation to ALI JAWAID, ELOÏSE A. KREMER, NANCY V.N. CARULLO AND
Pharmacokinetics 689 ISABELLE M. MANSUY
Population Pharmacoepigenomics in Relation to
Pharmacodynamics 689 Introduction 738
3D and 4D Chromatin Structures in the Nuclei of Cells Important Epigenetic Mechanisms for the Brain 738
in the Liver and Other Body Organs and Population Epigenetic Dysregulation in Neurodevelopmental
Pharmacoepigenomics 690 Disorders: The Example of Rett Syndrome 739
Population Pharmacoepigenomics in Relation to Epigenetic Dysregulation in Neurodegenerative
Adverse Drug Reactions and Drug Interactions 691 Disorders: The Example of Alzheimer’s Disease 742
Conclusions 691 Epigenetic Dysregulation in Psychiatric Disorders:
Population Pharmacoepigenomics Case Study 691 The Example of Depression 745
References 693 Epigenetic Dysregulation by Environmental Stress:
The Example of Early-life Stress 748
Conclusions and Outlook 749
VIII Summary
Research case study
750
751
Epigenetics and Human Disease Acknowledgments 752
References 752

35. Cancer Epigenetics 697

MARINA ALEXEEVA, MARCUS ROALSØ AND KJETIL SØREIDE 38. Epigenetics of Metabolic Diseases 761
LINN GILLBERG AND LINE HJORT
Introduction 697
Epigenetic Influences Over a Lifetime and Cancer Risk 698 Introduction 761
Epigenetics in Cancer: Remodelers, Writers, Readers, and Impact of Age and Lifestyle Factors on the Epigenome 762
Erasers 699 Epigenetic Memory, Prenatal Exposure, and Risk of
Genetic and Epigenetic Classification of Cancer 705 Metabolic Disease 766
Epigenetic Biomarkers in Cancer 708 Epigenetic Features of Metabolic Diseases 769
Epigenetics as Cancer Therapeutic Targets 709 Conclusions 771
Future Perspectives 710 References 772
References 711

39. Imprinting Disorders in Humans 779

36. The Role of Epigenetics in Autoimmune
THOMAS EGGERMANN
Disorders 715
KERSTIN KLEIN Introduction 779
Clinical Findings in Imprinting Disorders 779
Epigenetic Mechanisms Influence Autoimmune Processes 715 Molecular Findings in Imprinting Disorders 781
Mechanisms of Autoimmunity 716 Causes of Disturbed Imprinting 782
Epigenetics of Immune Cells 719 Cis-acting Factors 783
Epigenetics of Systemic Lupus Erythematosus 720 Trans-acting Factors 784
Epigenetics of Rheumatoid Arthritis 722 Maternal Effect Mutations and Multilocus Imprinting
Multiple Sclerosis 723 Disturbance 784
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 Contents xi
Translational Use of New Findings in ImpDis and New Chromatin-remodeling Agents, Combined Treatment, and
Methodologies 785 Targeted Therapy 822
Genetic and Reproductive Counseling 787 DNA Methylation/Demethylation and Combined Treatment 823
Clinical Management 787 Histone Modifications and Histone-modifying Enzymes for
Concluding Remarks 787 Epigenetic Treatment 828
References 787 Conclusions and Future Perspectives 833
Clinical Trial 833
References 837
IX
Epigenetic Therapy
X
40. Clinical Applications of Histone Deacetylase The Future of Epigenetics
Inhibitors 793
ROMAIN PACAUD, JOSE GARCIA, SCOTT THOMAS AND
PAMELA N. MUNSTER
42. New Directions for Epigenetics:
Application of Engineered DNA-binding
Introduction 793 Molecules to Locus-specific Epigenetic Research 843
HDACi for the Treatment of Hematological Malignancies 795
TOSHITSUGU FUJITA AND HODAKA FUJII
HDACi in the Treatment of Solid Tumors 801
Clinical Applications of HDACi for Noncancer Diseases 807 Introduction 843
Conclusions and the Future Directions of the Clinical General Information on Engineered DNA-binding
Applications of HDACi 809 Molecules 844
References 810 Locus-specific Epigenome Editing 845
Locus-specific Identification of Epigenetic Molecules
that Interact with Target Genomic Regions 858
41. Combination Epigenetic Therapy 821
Conclusions 862
RŪTA NAVAKAUSKIENĖ References 862
Introduction 821 Index 869
 List of contributors

Nobuyoshi Akimitsu Isotope Science Center, The Felice Elefant Department of Biology, Drexel University,
University of Tokyo, Tokyo, Japan Philadelphia, PA, United States
Marina Alexeeva Department of Gastrointestinal Surgery, Peter D. Fransquet School of Public Health and Preventive
Stavanger University Hospital, Stavanger, Norway; Medicine, Monash University, Melbourne, VIC, Australia
Gastrointestinal Translational Research Unit, Laboratory Hodaka Fujii Department of Biochemistry and Genome
for Molecular Biology, Stavanger University Hospital, Biology, Hirosaki University Graduate School of
Stavanger, Norway Medicine, Aomori, Japan
Juliana Almeida Centre of Natural Sciences and Toshitsugu Fujita Department of Biochemistry and
Humanities, Federal University of ABC, Sao Bernardo do Genome Biology, Hirosaki University Graduate School of
Campo, Brazil Medicine, Aomori, Japan
Rodolfo Daniel Ávila-Avilés Laboratory of Epigenetics of Leonardo Furci Plant Epigenetics Unit, Okinawa Institute
Skeletal Muscle Regeneration, Department of Genetics of Science and Technology Graduate University, Onna-
and Molecular Biology, Centre for Research and son, Okinawa, Japan
Advanced Studies-IPN, Mexico City, Mexico
Jose Garcia Division of Hematology and Oncology,
Jérémy Berthelier Plant Epigenetics Unit, Okinawa University of California, San Francisco, CA, United States
Institute of Science and Technology Graduate University,
Balaram Ghosh Epigenetic Research Laboratory,
Onna-son, Okinawa, Japan
Department of Pharmacy, Birla Institute of Technology
Akanksha Bhatnagar Department of Biology, Drexel and Science-Pilani Hyderabad Campus, Shamirpet,
University, Philadelphia, PA, United States Hyderabad, Telangana, India
Maria Boskovic Laboratory for Cancer Research, Linn Gillberg Department of Biomedical Sciences,
University of Split School of Medicine, Split, Croatia University of Copenhagen, Copenhagen, Denmark
Nancy V.N. Carullo Laboratory of Neuroepigenetics, Karen Giménez-Orenga Centro de Investigación
Brain Research Institute, Medical Faculty of the University Traslacional San Alberto Magno, Universidad Católica de
of Zurich, Zurich, Switzerland; Zurich Neuroscience Valencia San Vicente Mártir, Valencia, Spain
Center, ETH and University of Zurich, Zurich,
Courtney W. Hanna Centre for Trophoblast Research,
Switzerland
University of Cambridge, Cambridge, United Kingdom;
J. Armando Casas-Mollano BioTechnology Institute, Department of Physiology, Development and
University of Minnesota, Twin-Cities, Saint Paul, MN, Neuroscience, University of Cambridge, Cambridge,
United States United Kingdom; Epigenetics Programme, Babraham
Frances A. Champagne Department of Psychology, Institute, Cambridge, United Kingdom
University of Texas, Austin, TX, United States Zdenko Herceg International Agency for Research on
Taiping Chen The Ministry of Education Key Laboratory Cancer (IARC), Lyon, France
of Laboratory Medical Diagnostics, College of Laboratory J. Manuel Hernández-Hernández Instituto Politécnico
Medicine, Chongqing Medical University, Chongqing, P. Nacional 2508, San Pedro Zacatenco, Ciudad de México,
R. China México
Ravindresh Chhabra Department of Biochemistry, Central Line Hjort Department of Endocrinology, Copenhagen
University of Punjab, Ghudda, Punjab, India University Hospital, Copenhagen, Denmark
James P. Curley Department of Psychology, University of Xiaotong Hu Sir Run Run Shaw Hospital, Zhejiang
Texas, Austin, TX, United States University, Hangzhou, Zhejiang, P.R. China
Gareth W. Davison Faculty of Life and Health Sciences, Eveline M. Ibeagha-Awemu Sherbrooke Research and
Ulster University, Northern Ireland, United Kingdom Development Centre, Agriculture and Agri-Food Canada,
Gary L. Dunbar Field Neurosciences Institute, Saginaw, Sherbrooke, QC, Canada
MI, United States Ali Jawaid Laboratory of Neuroepigenetics, Brain Research
Thomas Eggermann Institut für Humangenetik, RWTH Institute, Medical Faculty of the University of Zurich,
Aachen, Aachen, Germany Zurich, Switzerland; Department of Health Sciences and

xiii
xiv List of contributors

Technology, Institute for Neuroscience, ETH Zurich, Pamela N. Munster Division of Hematology and Oncology,
Zurich, Switzerland; Zurich Neuroscience Center, ETH University of California, San Francisco, CA, United States
and University of Zurich, Zurich, Switzerland Rabih Murr Faculty of Medicine, Department of Genetic
Wei Jiang Frontier Science Center for Immunology and Medicine and Development, University of Geneva,
Metabolism, Medical Research Institute, Wuhan Geneva, Switzerland
University, Wuhan, P.R. China Rūta Navakauskienė Life Sciences Center, Vilnius
Oscar Juez Plant Epigenetics Unit, Okinawa Institute of University, Vilnius, Lithuania
Science and Technology Graduate University, Onna-son, Claudia Negrón-Lomas Laboratory of Epigenetics of
Okinawa, Japan Skeletal Muscle Regeneration, Department of Genetics
Ashley M. Karnay Department of Neurobiology & and Molecular Biology, Centre for Research and
Anatomy, Drexel University College of Medicine, Advanced Studies-IPN, Mexico City, Mexico
Philadelphia, PA, United States
Fereshteh S. Nugent Department of Pharmacology &
Kentaro Kawata Isotope Science Center, The University of Molecular Therapeutics, F. Edward Hebert School of
Tokyo, Tokyo, Japan; Cellular and Molecular Medicine, Uniformed Services University of the Health
Biotechnology Research Institute, National Institute of Sciences, Bethesda, MD, United States
Advanced Industrial Science and Technology (AIST),
Elisa Oltra Centro de Investigación Traslacional San
Tokyo, Japan
Alberto Magno, Universidad Católica de Valencia San
Hasan Khatib Department of Animal and Dairy Sciences, Vicente Mártir, Valencia, Spain; Department of Pathology,
University of Wisconsin, Madison, WI, United States School of Medicine and Health Sciences, Universidad
Eric W. Klee Division of Computational Biology, Católica de Valencia San Vicente Mártir, Valencia, Spain
Department of Quantitative Health Sciences, Mayo Clinic, Rena Onoguchi-Mizutani Isotope Science Center, The
Rochester, MN, United States University of Tokyo, Tokyo, Japan
Kerstin Klein Department of BioMedical Research, Nail Can Öztürk Department of Anatomy, Mersin
University of Bern, Bern, Switzerland; Department of University, Mersin, Turkey
Rheumatology and Immunology, Bern University
Romain Pacaud Division of Hematology and Oncology,
Hospital, Bern, Switzerland
University of California, San Francisco, CA, United States
Eloı̈se A. Kremer Laboratory of Neuroepigenetics, Brain
Research Institute, Medical Faculty of the University of Jacob Peedicayil Department of Pharmacology & Clinical
Zurich, Zurich, Switzerland; Zurich Neuroscience Center, Pharmacology, Christian Medical College, Vellore, Tamil
ETH and University of Zurich, Zurich, Switzerland Nadu, India

Ilkka Kronholm Department of Biological and Prasad Pethe Symbiosis Centre for Stem Cell Research
Environmental Science, University of Jyväskylä, (SCSCR), Symbiosis International University (SIU), Pune,
Jyväskylä, Finland Maharashtra, India
Ho-Sun Lee Interdisciplinary Program in Bioinformatics Gerd P. Pfeifer Department of Epigenetics, Van Andel
and Department of Statistics, Seoul National University, Institute, Grand Rapids, MI, United States
Seoul, Republic of Korea; Toxicology Division, National Sravani Pulya Epigenetic Research Laboratory, Department
Forensic Service Daegu Institute, Republic of Korea of Pharmacy, Birla Institute of Technology and Science-
Frédérique Magdinier Aix Marseille Univ, INSERM, Pilani Hyderabad Campus, Shamirpet, Hyderabad,
Marseille Medical Genetics, MMG, Marseille, France Telangana, India
Isabelle M. Mansuy Laboratory of Neuroepigenetics, Brain Tibor A. Rauch University of Pécs Medical School, Pécs,
Research Institute, Medical Faculty of the University of Hungary
Zurich, Zurich, Switzerland; Zurich Neuroscience Center, Marisol Resendiz Stark Neuroscience Research Institute
ETH and University of Zurich, Zurich, Switzerland Indiana University School of Medicine, Indianapolis, IN,
Rahia Mashoodh Department of Zoology, University of Uinted States
Cambridge, Cambridge, United Kingdom Marcus Roalsø Department of Gastrointestinal Surgery,
Mihaly Mezei Department of Pharmaceutical Sciences, Stavanger University Hospital, Stavanger, Norway;
Icahn School of Medicine at Mount Sinai, New York, NY, Gastrointestinal Translational Research Unit, Laboratory
United States for Molecular Biology, Stavanger University Hospital,
Maria Miah Department of Biology, Medgar Evers College, Stavanger, Norway; Department of Quality and Health
City University of New York, Brooklyn, NY, United States Technology, University of Stavanger, Stavanger Norway
Matin Miryeganeh Plant Epigenetics Unit, Okinawa Jérôme D. Robin Aix Marseille Univ, INSERM, Marseille
Institute of Science and Technology Graduate University, Medical Genetics, MMG, Marseille, France
Onna-son, Okinawa, Japan Julien Rossignol Central Michigan University, Mt.
Shiraz Mujtaba Department of Biology, Medgar Evers Pleasant, MI, United States
College, City University of New York, Brooklyn, NY, Joanne Ryan School of Public Health and Preventive
United States Medicine, Monash University, Melbourne, VIC, Australia
 List of contributors xv
Cı́ntia Barros Santos-Rebouças Department of Genetics, Nutrition Obesity Research Center, University of Alabama
Institute of Biology Roberto Alcantara Gomes, State at Birmingham, Birmingham, AL, United States;
University of Rio de Janeiro, Rio de Janeiro, Rio de Comprehensive Diabetes Center, University of Alabama
Janeiro, Brazil at Birmingham, Birmingham, AL, United States;
Hidetoshi Saze Plant Epigenetics Unit, Okinawa Institute University Wide Microbiome Center, University of
of Science and Technology Graduate University, Onna- Alabama at Birmingham, Birmingham, AL, United States
son, Okinawa, Japan Mark van der Giezen Department of Chemistry, Bioscience
Ryan D. Shepard Department of Pharmacology & and Environmental Engineering, University of Stavanger,
Molecular Therapeutics, F. Edward Hebert School of Stavanger, Norway; Biosciences, University of Exeter,
Medicine, Uniformed Services University of the Health Exeter, United Kingdom
Sciences, Bethesda, MD, United States; Synapse and Ludovica Vanzan Institute of Bioengineering, School of
Neural Circuit Research Section, National Institute of Life Sciences, Swiss Federal Institute of Technology
Neurological Disorders and Stroke, National Institutes of (EPFL), Lausanne, Switzerland
Health, Bethesda, MD, United States Günter Vogt Faculty of Biosciences, University of
Philippe Silar Université de Paris, Paris Cité, France Heidelberg, Heidelberg, Germany
Athena Sklias Center for Integrative Genomics, University Darryl S. Watkins Stark Neuroscience Research Institute
of Lausanne, Lausanne, Switzerland Indiana University School of Medicine, Indianapolis, IN,
Susan L. Slager Division of Computational Biology, Uinted States
Department of Quantitative Health Sciences, Mayo Clinic, Martin M. Watson Department of Chemistry, Bioscience
Rochester, MN, United States and Environmental Engineering, University of Stavanger,
Kjetil Søreide Department of Gastrointestinal Surgery, Stavanger, Norway
Stavanger University Hospital, Stavanger, Norway; Loo Keat Wei Faculty of Science, Department of Biological
Gastrointestinal Translational Research Unit, Laboratory Science, Universiti Tunku Abdul Rahman, Kampar, Perak,
for Molecular Biology, Stavanger University Hospital, Malaysia
Stavanger, Norway; Department of Clinical Medicine, Jo Wrigglesworth School of Public Health and Preventive
University of Bergen, Bergen, Norway Medicine, Monash University, Melbourne, VIC, Australia
Bhairavi Srinageshwar Central Michigan University, Mt. Toshimichi Yamada Isotope Science Center, The University
Pleasant, MI, United States of Tokyo, Tokyo, Japan
David M. Suter Institute of Bioengineering, School of Life Huihuang Yan Division of Computational Biology,
Sciences, Swiss Federal Institute of Technology (EPFL), Department of Quantitative Health Sciences, Mayo Clinic,
Lausanne, Switzerland Rochester, MN, United States
Kenzui Taniue Isotope Science Center, The University of Jie Yang Frontier Science Center for Immunology and
Tokyo, Tokyo, Japan Metabolism, Medical Research Institute, Wuhan
Scott Thomas Division of Hematology and Oncology, University, Wuhan, P.R. China
University of California, San Francisco, CA, United States Zhengzhou Ying Department of Epigenetics and Molecular
Shulan Tian Division of Computational Biology, Carcinogenesis, The University of Texas MD Anderson
Department of Quantitative Health Sciences, Mayo Clinic, Cancer Center, Houston, TX, United States
Rochester, MN, United States Ericka Zacarias BioTechnology Institute, University of
Trygve O. Tollefsbol Department of Biology, University of Minnesota, Twin-Cities, Saint Paul, MN, United States
Alabama at Birmingham, Birmingham, AL, United States; Feng C. Zhou Stark Neuroscience Research Institute
O’Neal Comprehensive Cancer Center, University of Indiana University School of Medicine, Indianapolis, IN,
Alabama at Birmingham, Birmingham, AL, United States; Uinted States; Department of Anatomy, Cell Biology and
Integrative Center for Aging Research, University of Physiology, IUSM, Indianapolis, IN, Uinted States
Alabama at Birmingham, Birmingham, AL, United States;
 S E C T I O N I

Overview

1. Epigenetics overview
This page intentionally left blank
 C H A P T E R

1
Epigenetics Overview
Trygve O. Tollefsbol1,2,3,4,5,6
1
Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States 2O’Neal
Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States 3Integrative
Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL, United States 4Nutrition Obesity
Research Center, University of Alabama at Birmingham, Birmingham, AL, United States 5Comprehensive Diabetes
Center, University of Alabama at Birmingham, Birmingham, AL, United States 6University Wide Microbiome Center,
University of Alabama at Birmingham, Birmingham, AL, United States

O U T L I N E

Introduction 3 Epigenetic Epidemiology 6

Molecular Mechanisms of Epigenetics 3 Epigenetics and Human Disease 7
Methods in Epigenetics 4 Epigenetic Therapy 7
Model Organisms of Epigenetics 5 The Future of Epigenetics 7
Factors Influencing Epigenetic Changes 5 Conclusion 8
Evolutionary Epigenetics 6 References 8

INTRODUCTION MOLECULAR MECHANISMS OF

EPIGENETICS
In 1942, Conrad Waddington first defined epige-
netics as the causal interactions between genes and DNA methylation is the most studied of epigenetic
their products that allow for the phenotypic expression processes. It most eukaryotes, DNA methylation
[1]. This term has now been somewhat redefined and consists of transfer of a methyl moiety from
although there are many variants of the definition S-adenosylmethionine (SAM) to the 5-position of cyto-
today, a consensus definition is that epigenetics is the sines in certain CpG dinucleotides. This important
collective heritable changes in phenotype due to pro- enzymatic transfer reaction is catalyzed by the DNA
cesses that arise independent of changes in the pri- methyltransferases (DNMTs). The three major DNMTs
mary DNA sequence. This heritability of epigenetic are DNMT1, 3A, and 3B. DNMT1 catalyzes what is
information was for many years thought to be limited called maintenance methylation, which occurs during
to mitotic cellular divisions. However, it is now appar- each cellular replication as the DNA duplicates. The
ent that epigenetic processes can be transferred meioti- other major DNMTs, 3A and 3B, are characterized by
cally in organisms from one generation to another their relatively higher de novo methylation activity.
[2,3]. This phenomenon was first described in plants This process leads to the introduction of
[4] and has been expanded to include yeast, Drosophila, 5-methylcytosines (5mCs) into the genome at sites that
mouse, and possibly humans [5 7]. were not previously methylated. Notably, the most

Handbook of Epigenetics.
DOI: https://doi.org/10.1016/B978-0-323-91909-8.00031-1 3 Copyright © 2023 Elsevier Inc. All rights reserved.
4 1. EPIGENETICS OVERVIEW

significant aspect of DNA methylation, which can also versatile and often plays a major role in epigenetic pro-
influence such processes as X-chromosome inactivation cesses. For instance, noncoding RNA (Chapter 4) includ-
and cellular differentiation, is its effects on gene ing both short (,200 nucleotides) and long ( . 200
expression. In general, the more methylated a nucleotides) forms, often share protein and RNA compo-
gene regulatory region, the more likely it is that the nents with the RNA interference (RNAi) pathway and
gene activity will become downregulated and vice ver- they may also influence more conventional aspects of
sa, although there are some exceptions to this dogma epigenetics such as DNA methylation and chromatin
[8]. Chapter 2 of this book reviews the mechanisms of marking. These effects appear to be wide-spread and
DNA methylation and demethylation during mamma- occur in organisms ranging from protists to humans.
lian development. Major changes in DNA methylation Notably, the noncoding RNAs may serve as therapeutic
occur during development and this is especially true targets for a number of human diseases and this area of
with respect to early embryonic development. Further, epigenetics is now attracting considerable attention.
the germ cells also display many changes during Prions are fascinating in that they can influence epige-
gametogenesis. Recent advances have highlighted netic processes independent of DNA and chromatin. In
important roles of the ten-eleven translocation family Chapter 5 it is shown that structural heredity also is
of dioxygenases. These enzymes convert 5mC to important in epigenetic expression where alternative
5-hydroxymethylcytosie (5hmC), 5-formylcytosine states of macromolecular complexes or regulatory net-
(5fC), and 5-carboxylcytosine (5caC) and appear to works can have a major effect on phenotypic expression
play important roles in the dramatic DNA demethyla- independent of changes in DNA sequences. The prion
tion that occurs during early development. The 5mC proteins are able to switch their structure in an autocata-
oxidized derivatives may also serve as epigenetic lytic manner that can not only influence epigenetic
marks that modulate chromatin regulation. expression, but also lead to human disease although the
There are additional important epigenetic changes full potential of prions in epigenetic processes is still on
that occur in the genome. For example, chromatin the horizon.
changes are another central epigenetic process that The position of a gene in a given chromosome can
have an impact not only on gene expression, but also also greatly influence its expression (Chapter 6). Upon
many other biological processes. Posttranslational rearrangement, a gene may be relocated to a hetero-
modifications of histones such as acetylation and chromatic region of the genome leading to gene silenc-
methylation occur in a site-specific manner and often ing. Moreover, a change in position of a regulatory
influence the binding and activities of other proteins element may affect the maintenance of chromatin
that influence gene regulation. The histone acetyltrans- architecture and subsequently cellular functioning.
ferases catalyze histone acetylation and the histone Polycomb mechanisms are another aspect of epige-
deacetylases (HDACs) result in removal of acetyl netics that control all of the major cellular differentia-
groups from key histones that comprise the chromatin. tion pathways and are also involved in cell fate.
These modifications can occur at numerous sties in the Polycomb protein repression is very dynamic and can
histones and are most common in the amino terminal be easily reversed by activators. They also raise the
regions of these proteins as discussed in Chapter 3. In threshold of the signals or activators required for tran-
general, increased histone acetylation is associated scriptional activation which places these fascinating
with greater gene activity and vice versa. Methylation proteins within the realm of epigenetic processes.
of histones has variable effects on gene activity. Lysine Polycomb complexes can generate H2A ubiquitylation
4 (K4) methylation of histone H3 is often associated and H3K27 methylation that often mediate their
with increasing gene activity whereas methylation of repressive functions and H3K27 may serve as an epi-
lysine 9 (K9) of histone H3 may lead to transcriptional genetic memory for Polycomb repression as described
repression. There is also considerable crosstalk in Chapter 7. Therefore, although DNA methylation
between DNA methylation and histone modifications and histone modifications are mainstays of epigenetics,
[9] such that cytosine methylation may increase the recent advances have greatly expanded the field of epi-
likelihood of H3K9 methylation and H3K9 methylation genetics to include many other processes such as non-
may promote cytosine methylation. In addition, coding RNA, prions, chromosome position effects and
histone-modifying epigenetic enzymes have recently Polycomb mechanisms.
been identified that may have key roles that are not
dependent on their catalytic activity (Chapter 3).
Among the most exciting advances in epigenetics METHODS IN EPIGENETICS
have been the discoveries of many other processes
besides DNA methylation, and histone modifications Numerous advances in epigenetics that have driven
impacting the epigenetic behavior of cells. RNA is highly this field for the past two decades can be traced back

I. OVERVIEW
 FACTORS INFLUENCING EPIGENETIC CHANGES 5
to the technological breakthroughs that have made the neurological disorders. Perhaps the most useful model
many discoveries possible. We now have a wealth of system in epigenetics to date is the mouse model
information about key gene-specific epigenetic changes (Chapter 14). Numerous different mouse models have
that occur in a myriad of biological processes. been developed that are important in many different
However, among the most exciting advances have epigenetic processes such as transgenerational epige-
been important breakthroughs in analyses of the netics and imprinting and these models have potential
methylome at high resolution. High-throughput in illuminating a number of human diseases. Analyses
sequencing, which has largely replaced microarray of epigenetic processes in development and health of
platforms, has made possible new techniques to ana- offspring can also be facilitated through the use of
lyze genome-wide features of epigenetics that are mouse models. Plant models (Chapter 15) are of great
based on uses of methylation-sensitive restriction importance in epigenetics due in part to their plasticity
enzymes, sodium bisulfite conversion and affinity cap- and their ability to silence transposable elements.
ture with antibodies or proteins that select methylated RNAi silencing in plants has been at the forefront of
DNA sequences. Tiling arrays may be employed for epigenetics and plant models will likely lead the way
analysis of chromosomal segments or the whole in several other epigenetic processes in the future. Use
genome and whole genome high-throughput sequenc- of plant models has also facilitated the development of
ing is now a staple for reliable and specific methylomic targeted epigenome editing in plants that may have
analyses. Additionally, single-cell analyses of DNA great significance in enhancing crop performance.
methylation patterns by whole genome epigenetic Thus, model development, like the advances in techni-
analyses are emerging as described in Chapter 8. ques, have made many of the most exciting discoveries
Chromatin immunoprecipitation and sequencing in epigenetics possible for a number of years.
(ChIP-seq) is frequently used in epigenetic analyses
and can also be applied to single cells as well as used
for mapping two modifications simultaneously as FACTORS INFLUENCING EPIGENETIC
described in Chapter 9. Likewise, genome-wide CHANGES
expression analyses of RNAs have been made possible
with RNA-seq that allows detection of a myriad of The functions of epigenetics are indeed numerous
noncoding RNAs (Chapter 10). Since there has been and it would be next to impossible to do complete jus-
much information derived from epigenomic tice in one book to this ever-expanding field. However,
approaches, methods to analyze data from ChIP-seq Chapters 16 25 illustrate a few of the many different
and RNA-seq, for example, are becoming increasingly functions that epigenetics mediates. For example,
important and are delineated in Chapter 11. Notably, Chapter 16 reviews the role of epigenetics in early
developments in the tools for assessing epigenetic development and illustrates that both gene-specific
information have been and will continue to be an and global changes in DNA methylation are central to
important driving force in advancing epigenetics. embryonic development. In addition, perturbations
mediated by processes such as stress during develop-
ment may lead to disease formation later in life.
MODEL ORGANISMS OF EPIGENETICS Chapter 17 reviews epigenetic biomarkers that are also
very important and serve the key function of inform-
Epigenetic processes are wide-spread and much of ing the staging and classification of disease as well as
our extant knowledge about epigenetics has been guiding clinical management. Another factor that can
derived from model systems, both typical and unique. significantly influence epigenetic changes is the activ-
The ease of manipulation of prokaryotic organisms has ity of transposable elements. These elements insert into
facilitated discoveries in the molecular mechanisms of coding or noncoding regions of the genome and can
basic epigenetic processes. Although prokaryotic also exert effects in cis by their insertion or altering of
organisms do not contain chromatin, some bacteria are the epigenetic state of the insertional site itself as
capable of encoding factors which lead to posttransla- described in Chapter 18. These mechanisms of trans-
tional modifications of an epigenetic nature as posable elements have not only shaped evolution, but
described in Chapter 12. Drosophila is a mainstay can also contribute to epigenetic-based diseases.
model in biology in general and the epigenetics field is Epigenetics is intricately linked to changes in the
not an exception in this regard. For example, metabolism of organisms and these two processes can-
Chapter 13 discusses how use of Drosophila as a model not be fully understood separately. SAM is a universal
organism has significantly increased knowledge of methyl donor and drives many epigenetic processes;
chromatin organization and may have powerful poten- the importance of SAM in epigenetic mechanisms is
tial in facilitating understanding of the epigenetics of vast. Metabolic functions can also influence the

I. OVERVIEW
6 1. EPIGENETICS OVERVIEW

chromatin which is a major mediator of epigenetic pro- aging, certain epigenetic-based diseases, and may
cesses (Chapter 19). It is now apparent that various have prognostic capacity for age-related diseases. It
environmental influences such as diet and changes in is therefore apparent that epigenetics influences
metabolic compounds can regulate the many enzymes numerous different functions and it is highly likely
that modify histones in mammals. Thus, metabolic that many additional functions of epigenetics will be
processes impacted by dietary changes can greatly discovered in the future.
influence both DNA methylation and chromatin remo-
deling, the two major epigenetic mediators, and signif-
icantly influence gene regulation in both health and EVOLUTIONARY EPIGENETICS
disease.
Stem cells rely in part on signals from the environ- Although many think of epigenetic processes as
ment and epigenetic mechanisms have central roles in being inherent and static to a specific organism, it is
how stem cells respond to environmental influences apparent that epigenetics have been a major force
(Chapter 20) and how therapeutic roles of stem cells behind the evolutionary creation of new species.
may contribute to management of many diseases such Chapter 26 reveals that epigenetic mediators such as
as multiple sclerosis, Huntington disease and Parkinson H3K4 and H3K27 methyltransferases have significantly
disease. Regenerative medicine is dependent upon stem impacted plant evolution. The expansion of gene fami-
cells. Regulation of muscle regenerative abilities lies of these enzymes may have allowed for changes in
involves key changes in the epigenome that regulate chromatin regulation of new genes and pathways that
gene expression and may have potential use to treat have modified plant evolution. The epigenetic machin-
skeletal muscle diseases (Chapter 21). Some of the basic ery has also played a major role in the evolution of ani-
tenets of epigenetics were first realized through studies mals. As described in Chapter 27, DNA methylation
of X-chromosome inactivation which allows for dosage may serve as a driver of evolution through its effects
compensation for X-linked gene expression between on gene regulation. Vertebrates have evolved genome-
males and females. As discussed in Chapter 22, wide methylation while invertebrates are characterized
advances in the study of the epigenetics of X- by mosaic DNA methylation patterns. Epigenotype
chromosome inactivation have revealed that epigenetic diversification followed by genetic fixation could be a
modification of the inheritance mode of X-driven phe- major mechanism of evolution that is currently under-
notypes can impact the plasticity of human conditions studied and may receive increasing attention in future
and may lead to new strategies for treating dominant analyses of epigenetics in evolutionary processes.
X-linked disorders in females. Profound new discover- Adaptive evolution by natural selection requires heri-
ies have occurred in the area of the epigenetics of mem- tability, and spontaneous epigenetic changes may have
ory processes. Recent exciting discoveries have shown been important in adaptive evolution, although there
that gene regulation through epigenetic mechanisms is are important differences between genetic variation
necessary for changes in adult brain function and and epigenetic variation with respect to supply and
behavior based on life experiences (Chapter 23). stability of epigenetic mutations (Chapter 28).
Moreover, new drugs that impact epigenetic mechan-
isms may have future uses in treating or alleviating cog-
nitive dysfunction. Transgenerational inheritance EPIGENETIC EPIDEMIOLOGY
(Chapter 24) is also a form of memory based in part on
epigenetics in that early life experiences that impact A very new and exciting area within the field of epi-
epigenetic markers can greatly influence adult health genetics is the impact of epigenetic mechanisms on
and risk for diseases. In addition, the aging process livestock breeding. Chapter 29 indicates that the breed-
is a form of epigenetic memory and experience in ing programs of livestock that are currently in place
that our genes are epigenetically modified from our account for only part of the phenotypic variance in
parents as well as during our entire life spans that traits and that epigenetic factors of variance need fur-
can significantly impact the longevity of humans as ther consideration. In fact, livestock epigenetics may
well as our risk for the many age-related diseases, have a major impact on the growth and development
many of which are also epigenetically based. As of livestock and profoundly affect phenotypic out-
reviewed in Chapter 25, there has been a surge of comes. Dietary factors are highly variable not only
interest in DNA methylation biomarkers of aging between individuals but also among human popula-
which are referred to as “epigenetic clocks.” tions and various nonhuman species. Many studies
Environmental factors have been found to influence have shown that the diet has a profound effect on the
these epigenetic biomarkers and they have consider- epigenetic expression of the genome and therefore
able potential for identifying accelerated epigenetic on the phenotype. An important example of this

I. OVERVIEW
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plight they were in. “Good gracious, brothers!” exclaimed some of
them to the others, “we have made a fine mess of our white
plumage!” And they gave it up.
Then the Crows rushed in and flapped against the light, but they
could not put it out; and although they grew blacker and blacker,
they would not give it up. So they became as black as crows are
now; and ever since then eagles have been speckled with brown and
black, and crows have been black, even to the tips of their beaks.
And whenever in the Sacred Drama Dance of our people old Mítsina
appears, he sings the doleful song and carries the light of pitch pine.
He goes naked, with the exception of a wretched old cloth at his
loins; and he wears a mask with deep holes for eyes, blood
streaming from them.
Thus shortens my story.
 HOW THE TWINS OF WAR AND
CHANCE, ÁHAIYÚTA AND MÁTSAILÉMA,
FARED WITH THE UNBORN-MADE MEN
OF THE UNDERWORLD[26]
[26] Reprinted from the Journal of American Folk-Lore, vol. v.,
No. 16, pp. 49-56. Back

Translator’s Introduction

H
ERETOFORE I have withheld from publication such single
examples of Zuñi folk-lore as the following, in order that the
completer series might be brought forth in the form of an
unbroken collection, with ample introductory as well as
supplementary chapters, essential to the proper understanding by
ourselves of the many distinctively Zuñi meanings and conceptions
involved in the various allusions with which any one of them teems.
Yet, to avoid encumbering the present example with any but the
briefest of notes, I must ask leave to refer the reader to the more
general yet detailed chapters I have already written in the main, and
with which, I have reason to hope, I will ere long be able to present
the tales in question. Meanwhile, I would refer likewise to the essay
I have recently prepared for the Thirteenth Annual Report of the
Bureau of American Ethnology, on Zuñi Creation Myths in their
relation to primitive dance and other dramaturgic ceremonies.
Ever one of my chief story-tellers was Waíhusiwa,—of the priestly kin
of Zuñi. He had already told me somewhat more than fifty of the folk
tales, long and short, of his people, when one night I asked him for
“only one more story of the grandfathers.” Wishing to evade me, he
replied with more show than sincerity:
“There is a North, and of it I have told you té-la-p’-na-we.[27] There
is a West; of it also I have told you té-la-p’-na-we. There are the
South and East; of them likewise have I told you té-la-p’-na-we.
Even of the Above have I not but lately told you of the youth who
made love to his eagle and dwelt apace in the Sky-world? And of the
great World-embracing Waters? You have been told of the hunter
who married the Serpent-maiden and journeyed to the Mountain of
Sunset. Now, therefore, my word-pouch is as empty as the food-
pack of a lost hunter, and—”
[27] From té-na-la-a, “time or times of,” and pé-na-we, words or
speeches (tales): “tales of time.” Back

“Feel in the bottom of it, then,” interposed old Pálowahtiwa, who

was sitting near, “and tell him of the Underworld.”
“Hi-ta! [Listen!] brother younger,” said Waíhusiwa, nonplussed but
ever ready. “Did you ever hear tell of the people who could not
digest, having, forsooth, no proper insides wherewithal to do so? Did
you ever hear of them, brother younger?”
“Nay, never; not even from my own grandfathers,” said I. “Sons éso
to your story; short be it or long.”[28]
[28] The invariable formula for beginning a folk tale is, by the
raconteur: “Són ah-tchi!” (“Let us take up”)—té-la-p’-ne, or “a folk
tale,” being understood. To this the auditors or listeners respond:
“É-so!” (“Yea, verily.”) Again, by the raconteur: “Sons i-nó-o-to-
na! Tem,” etc. (“Let us (tell of) the times of creation! When,” etc.)
Again, by the listeners: “Sons éso! Te-ä-tú!” (“Yea, let us, verily!
Be it so.”) Back

“Sons éso tse-ná!” (“Cool your ‘sons éso!’ and wait till I begin.”)—
F. H. C.
 Zuñi Introduction
It seems—so the words of the grandfathers say—that in the
Underworld were many strange things and beings, even villages of
men, long ago. But the people of those villages were unborn-made,
—more like the ghosts of the dead than ourselves, yet more like
ourselves than are the ghosts of the dead, for as the dead are more
finished of being than we are, they were less so, as smoke, being
hazy, is less fine than mist, which is filmy; or as green corn, though
raw, is soft like cooked corn which is done (like the dead), and as
both are softer than ripe corn which, though raw, is hardened by
age (as we are of meat).
And also, these people were, you see, dead in a way, in that they
had not yet begun to live, that is, as we live, in the daylight fashion.
And so, it would seem, partly like ourselves, they had bodies, and
partly like the dead they had no bodies, for being unfinished they
were unfixed. And whereas the dead are like the wind, and take
form from within of their own wills (yän′te-tseman), these people
were really like the smoke,[29] taking form from without of the
outward touching of things, even as growing and unripe grains and
fruits do.
[29] The Zuñi classification of states of growth or being is as
elaborate as that of relative space in their mythology—both
extremely detailed and systematic, yet, when understood, purely
primitive and simple. The universe is supposed to have been
generated from haze (shí-wai-a) produced by light (of the All-
container, Sun-father) out of darkness. The observed analogy of
this in nature is the appearance of haze (both heat and steam)
preceding growth in springtime; the appearance of the world, of
growing and living things, through mist seemingly rising out of
the darkness each morning. In harmony with this conception of
the universe is the correlative one that every being (as to soul, at
least) passes through many successive states of becoming,
always beginning as a shí-u-na hâ-i (haze being), and passing
through the raw or soft (k’ya-pi-na), the formative (k’yaí-yu-na),
variable (thlím-ni-na), fixed or done (ak-na), and finished or dead
 (ä-shï-k’ya) states; whilst the condition of the surpassing beings
(gods) may be any of these at will (i-thlim-na, or thlim-nah-na,
etc.). There are many analogies of this observed by the Zuñi,
likening, as he does, the generation of being to that of fire with
the fire-drill and stick. The most obvious of these is the
appearance, in volumes, of “smoke-steam” or haze just previously
to ignition, and its immediate disappearance with ignition. Further,
the succession of beings in the becoming of a complete being
may be regarded as an orderly personification of growth
phenomena as observed in plants and seeds; for example, in
corn, which is characterized by no fewer than thirteen mystic
names, according to its stages of growth. This whole subject is
much more fully and conclusively set forth in the writings to which
I have already referred. Back

Well, in consequence, it was passing strange what a state they were

in! Bethink ye! Their persons were much the reverse of our own, for
wherein we are hard, they were soft—pliable. Wherein we are most
completed, they were most unfinished; for not having even the
organs of digestion, whereby we fare lustily, food in its solidity was
to them destructive, whereas to us it is sustaining. When, therefore,
they would eat, they dreaded most the food itself, taking thought
not to touch it, and merely absorbing the mist thereof. As fishes fare
chiefly on water, and birds on air, so these people ate by gulping
down the steam and savor of their cooked things whilst cooking or
still hot; then they threw the real food away, forsooth!

The Tale

N
OW, the Twain Little-ones, Áhaiyúta and Mátsailéma,[30] were
ever seeking scenes of contention; for what was deathly and
dreadful to others was lively and delightful to them; so that
cries of distress were ever their calls of invitation, as to a feast or
dance is the call of a priest to us.
[30] For the mythic origin of these two chief gods under the Sun,
as his right- and left-hand being, their relation to chance, war,
 games, etc., I again refer the reader to the Zuñi Creation Myths.
Back

On a day when the world was quiet, they were sitting by the side of
a deep pool. They heard curious sounds coming up through the
waters, as though the bubbles were made by moans of the waters
affrighted.
“Uh!” cried the elder. “What is that?”
The younger brother turned his ear to the ground and listened.
“There is trouble down there, dire trouble, for the people of the
Underworld are shrieking war-cries like daft warriors and wailing like
murder-mourners. What can be the matter? Let us descend and
see!”
“Just so!” said Áhaiyúta.
Then they covered their heads with their cord-shields[31]—turned
upside down—and shut their eyes and stepped into the deep pool.
[31] Pi-a-la-we (cord or cotton shields), evidently an ancient style
of shield still surviving in the form of sacrificial net-shields of the
Priesthood of the Bow. But the shields of these two gods were
supposed to have been spun from the clouds which, supporting
the sky-ocean, that in turn supported the sky-world (as this world
is believed to be supported by under-waters and clouds), were
hence possessed of the power of floating—upward when turned
up, downward when reversed. Back

“Now we are in the dark,” said they, “like the dark down there. Well,
then, by means of the dark let us go down”—for they had wondrous
power, had those Twain; the magic of in-knowing-how thought had
they.
Down, like light through dark places, they went; dry through the
waters; straight toward that village in the Underworld.
“Whew! the poor wretches are already dead,” cried they, “and
rotting”—for their noses were sooner accustomed to the dark than
their eyes, which they now opened.
“We might as well have spared ourselves the coming, and stayed
above,” said Áhaiyúta.
“Nay, not so,” said Mátsailéma. “Let us go on and see how they
lived, even if they are dead.”
“Very well,” said the elder; and as they fared toward the village they
could see quite plainly now, for they had made it dark (to
themselves) by shutting their eyes in the daylight above, so now
they made it light (to themselves) by opening their eyes in the
darkness below and simply looking,—it was their way, you know.
“Well, well!” said Mátsailéma, as they came nearer and the stench
doubled. “Look at the village; it is full of people; the more they smell
of carrion the more they seem alive!”
“Yes, by the chut of an arrow!” exclaimed Áhaiyúta. “But look here!
It is food we smell—cooked food, all thrown away, as we throw away
bones and corn-cobs because they are too hard to eat and profitless
withal. What, now, can be the meaning of this?”
“What, indeed! Who can know save by knowing,” replied the
younger brother. “Come, let us lie low and watch.”
So they went very quietly close to the village, crouched down, and
peered in. Some people inside were about to eat. They took fine
food steaming hot from the cooking-pots and placed it low down in
wide trenchers; then they gathered around and sipped in the steam
and savor with every appearance of satisfaction; but they were as
chary of touching the food or of letting the food touch them as
though it were the vilest of refuse.
“Did you see that?” queried the younger brother. “By the delight of
death,[32] but—”
[32] Hé-lu-ha-pa; from hé-lu, or é-lu, “hurrah,” or “how
delightful!”—and há-pa, a corpse-demon, death. Back
“Hist!” cried the elder. “If they are people of that sort, feeding upon
the savor of food, then they will hear the suggestions of sounds
better than the sounds themselves, and the very demon fathers
would not know how to fare with such people, or to fight them,
either!”
Hah! But already the people had heard! They set up a clamor of war,
swarming out to seek the enemy, as well they might, for who would
think favorably of a sneaking stranger under the shade of a house-
wall watching the food of another? Why, dogs growl even at their
own offspring for the like of that!
“Where? Who? What is it?” cried the people, rushing hither and
thither like ants in a shower. “Hah! There they are! There! Quick!”
cried they, pointing to the Twain, who were cutting away to the
nearest hillock. And immediately they fell to singing their war-cry.

“Ha-a! Sús-ki!
Ó-ma-ta
Há-wi-mo-o!
Ó-ma-ta,
Ó-ma-ta Há-wi-mo!”[33]

sang they as they ran headlong toward the Two, and then they
began shouting:
“Tread them both into the ground! Smite them both! Fan them out!
Ho-o! Ha-a! Há-wi-mo-o ó-ma-ta!”
[33] This, like so many of the folk-tale songs, can only be
translated etymologically or by extended paraphrasing. Such
songs are always jargonistic, either archaic, imitative, or adapted
from other languages of tribes who possibly supplied incidents to
the myths themselves; but they are, like the latter, strictly
harmonized with the native forms of expression and phases of
belief. Back
But the Twain laughed and quickly drew their arrows and loosed
them amongst the crowd. P’it! tsok! sang the arrows through and
through the people, but never a one fell.
“Why, how now is this?” cried the elder brother.
“We’ll club them, then!” said Mátsailéma, and he whiffed out his
war-club and sprang to meet the foremost whom he pummelled well
and sorely over the head and shoulders. Yet the man was only
confused (he was too soft and unstable to be hurt); but another,
rushing in at one side, was hit by one of the shield-feathers and fell
to the ground like smoke driven down under a hawk’s wing.
“Hold, brother, I have it! Hold!” cried Áhaiyúta. Then he snatched up
a bunch of dry plume-grass and leaped forward. Swish! Two ways he
swept the faces and breasts of the pursuers. Lo! right and left they
fell like bees in a rain-storm, and quickly sued for mercy, screeching
and running at the mere sight of the grass-straws.
“You fools!” cried the brothers. “Why, then, did ye set upon us? We
came for to help you and were merely looking ahead as becomes
strangers in strange places, when, lo! you come running out like a
mess of mad flies with your ‘Ha-a sús-ki ó-ma-ta!’ Call us coyote-
sneaks, do you? But there! Rest fearless! We hunger; give us to eat.”
So they led the Twain into the court within the town and quickly
brought steaming food for them.
They sat down and began to blow the food to cool it, whereupon the
people cried out in dismay: “Hold! Hold, ye heedless strangers; do
not waste precious food like that! For shame!”
“Waste food? Ha! This is the way we eat!” said they, and clutching
up huge morsels they crammed their mouths full and bolted them
almost whole.
The people were so horrified and sickened at sight of this, that some
of them sweated furiously,—which was their way of spewing—whilst
others, stouter of thought, cried: “Hold! hold! Ye will die; ye will
surely sicken and die if the stuff do but touch ye!”
“Ho! ho!” cried the Twain, eating more lustily than ever. “Eat thus
and harden yourselves, you poor, soft things, you!”
Just then there was a great commotion. Everyone rushed to the
shelter of the walls and houses, shouting to them to leave off and
follow quickly.
“What is it?” asked they, looking up and all around.
“Woe, woe! The gods are angry with us this day, and blowing arrows
at us. They will kill you both! Hurry!” A big puff of wind was blowing
over, scattering slivers and straws before it; that was all!
“Brother,” said the elder, “this will not do. These people must be
hardened and be taught to eat. But let us take a little sleep first,
then we will look to this.”
They propped themselves up against a wall, set their shields in front
of them, and fell asleep. Not long after they awakened suddenly.
Those strange people were trying to drag them out to bury them,
but were afraid to touch them now, for they thought them dead
stuff, more dead than alive.
The younger brother punched the elder with his elbow, and both
pretended to gasp, then kept very still. The people succeeded at last
in rolling them out of the court like spoiling bodies, and were about
to mingle them with the refuse when they suddenly let go and set
up a great wail, shouting “War! Murder!”
“How now?” cried the Twain, jumping up. Whereupon the people
stared and chattered in greater fright than ever at seeing the dead
seemingly come to life!
“What’s the matter, you fool people?”
“Akaa kaa,” cried a flock of jays.
“Hear that!” said the villagers. “Hear that, and ask what’s the
matter! The jays are coming; whoever they light on dies—run you
two! Aii! Murder!” And they left off their standing as though chased
by demons. On one or two of the hindmost some jays alighted. They
fell dead as though struck by lightning!
“Why, see that!” cried the elder brother—“these people die if only
birds alight on them!”
“Hold on, there!” said the younger brother. “Look here, you fearsome
things!” So they pulled hairs from some scalp-locks they had, and
made snares of them, and whenever the jays flew at them they
caught them with the nooses until they had caught every one. Then
they pinched them dead and took them into the town and roasted
them. “This is the way,” said they, as they ate the jays by morsels.
And the people crowded around and shouted: “Look! look! why, they
eat the very enemy—say nothing of refuse!” And although they
dreaded the couple, they became very conciliatory and gave them a
fit place to bide in.
The very next day there was another alarm. The Two ran out to
learn what was the matter. For a long time they could see nothing,
but at last they met some people fleeing into the town. Chasing after
them was a cooking-pot with earrings of onions.[34] It was boiling
furiously and belching forth hot wind and steam and spluttering
mush in every direction. If ever so little of the mush hit the people
they fell over and died.
[34] The onion here referred to is the dried, southwestern leek-
clove, which is so strong and indigestible that, when eaten raw
and in quantity, gives rise to great distress, or actually proves
fatal to any but mature and vigorous persons. This, of course,
explains why it was chosen for its value as a symbol of the vigor
(or “daylight perfection” and invincibility) of the Twin gods. Back

“He!” cried the Twain;

 “Té-k’ya-thla-k’ya
Í-ta-wa-k’ya
Äsh′-she-shu-kwa!

—As if food-stuff were made to make people afraid!” Whereupon

they twitched the earrings off the pot and ate them up with all the
mush that was in the pot, which they forthwith kicked to pieces
vigorously.
Then the people crowded still closer around them, wondering to one
another that they could vanquish all enemies by eating them with
such impunity, and they begged the Twain to teach them how to do
it. So they gathered a great council of the villagers, and when they
found that these poor people were only half finished, ... they cut
vents in them (such as were not afraid to let them), ... and made
them eat solid food, by means of which they were hardened and
became men of meat then and there, instead of having to get killed
after the manner of the fearful, and others of their kind beforetime,
in order to ascend to the daylight and take their places in men born
of men.
And for this reason, behold! a new-born child may eat only of wind-
stuff until his cord of viewless sustenance has been severed, and
then only by sucking milk or soft food first and with much distress.
Behold! And we may now see why, like new-born children are the
very aged; childish withal—á-ya-vwi[35];—not only toothless, too,
but also sure to die of diarrhœa if they eat ever so little save the soft
parts and broths of cooked food. For are not the babes new-come
from the Shi-u-na[36] world; and are not the aged about to enter the
Shi-po-lo-a[37] world, where cooked food unconsumed is never
heeded by the fully dead?
[35] Dangerously susceptible, tender, delicate. Back
[36] Hazy, steam-growing. Back
 [37] Mist-enshrouded. Back

Thus shortens my story.

 THE COCK AND THE MOUSE
Note.—While on their pilgrimage to the “Ocean of Sunrise” in the
summer of 1886, three Zuñis—Pálowahtiwa, Waíhusiwa, and
Héluta—with Mr. Cushing, were entertaining their assembled
friends at Manchester-by-the-Sea with folk tales, those related
by the Indians being interpreted by Mr. Cushing as they were
uttered. When Mr. Cushing’s turn came for a story he responded
by relating the Italian tale of “The Cock and the Mouse” which
appears in Thomas Frederick Crane’s Italian Popular Tales. About
a year later, at Zuñi, but under somewhat similar circumstances,
Waíhusiwa’s time came to entertain the gathering, and great
was Mr. Cushing’s surprise when he presented a Zuñi version of
the Italian tale. Mr. Cushing translated the story as literally as
possible, and it is here reproduced, together with Mr. Crane’s
translation from the Italian, in order that the reader may not
only see what transformation the original underwent in such a
brief period, and how well it has been adapted to Zuñi
environment and mode of thought, but also to give a glimpse of
the Indian method of folk-tale making.—Editor.

Italian Version

O
NCE upon a time there were a cock and a mouse. One day the
mouse said to the cock: “Friend Cock, shall we go and eat
some nuts on yonder tree?” “As you like.” So they both went
under the tree and the mouse climbed up at once and began to eat.
The poor cock began to fly, and flew and flew, but could not come
where the mouse was. When it saw that there was no hope of
getting there, it said: “Friend Mouse, do you know what I want you
to do? Throw me a nut.” The mouse went and threw one and hit the
cock on the head. The poor cock, with its head all broken and
covered with blood, went away to an old woman. “Old aunt, give me
some rags to cure my head.” “If you will give me two hairs I will give
you the rags.” The cock went away to a dog. “Dog, give me two
hairs; the hairs I will give the old woman; the old woman will give
me rags to cure my head.” “If you will give me a little bread,” said
the dog, “I will give you the hairs.” The cock went away to a baker.
“Baker, give me bread; I will give bread to the dog; the dog will give
hairs; the hairs I will carry to the old woman; the old woman will
give me rags to cure my head.” The baker answered: “I will not give
you bread unless you give me some wood.” The cock went away to
the forest. “Forest, give me some wood; the wood I will carry to the
baker; the baker will give me some bread; the bread I will give to
the dog; the dog will give me hairs; the hairs I will carry to the old
woman; the old woman will give me rags to cure my head.” The
forest answered: “If you will bring me a little water, I will give you
some wood.” The cock went away to a fountain. “Fountain, give me
water; water I will carry to the forest; forest will give wood; wood I
will carry to the baker; baker will give bread; bread I will give dog;
dog will give hairs; hairs I will give old woman; old woman will give
rags to cure my head.” The fountain gave him water; the water he
carried to the forest; the forest gave him wood; the wood he carried
to the baker; the baker gave him bread; the bread he gave to the
dog; the dog gave him the hairs; the hairs he carried to the old
woman; the old woman gave him the rags; and the cock cured his
head.

Zuñi Version

T
HUS it was in the Town of the Floods Abounding,[38] long ago.
There lived there an old woman, so they say, of the Italia-kwe,
[39] who, in the land of their nativity, are the parental brothers
of the Mexicans, it is said. Now, after the manner of that people, this
old woman had a Tâkâkâ Cock which she kept alone so that he
would not fight the others. He was very large, like a turkey, with a
fine sleek head and a bristle-brush on his breast like a turkey-cock’s
too, for the Tâkâkâ-kind were at first the younger brothers of the
Turkeys, so it would seem.
[38] Venice. Back
[39] “Italy-people.” Back

Well, the old woman kept her Cock in a little corral of tall close-set
stakes, sharp at the top and wattled together with rawhide thongs,
like an eagle-cage against a wall, only it had a little wicket also
fastened with thongs. Now, try as he would, the old Tâkâkâ Cock
could not fly out, for he had no chance to run and make a start as
turkeys do in the wilds, yet he was ever trying and trying, because
he was meat-hungry—always anxious for worms;—for, although the
people of that village had abundant food, this old woman was poor
and lived mainly on grain-foods, wherefore, perforce, she fed the old
Tâkâkâ Cock with the refuse of her own eatings. In the morning the
old woman would come and throw this refuse food into the corral
cage.
Under the wall near by there lived a Mouse. He had no old
grandmother to feed him, and he was particularly fond of grain food.
When, having eaten his fill, the old Cock would settle down, stiff of
neck and not looking this side nor that, but sitting in the sun kâ-tâ-
kâ-tok-ing to himself, the little Mouse would dodge out, steal a bit of
tortilla or a crumb, and whisk into his hole again. Being sleepy, the
Tâkâkâ Cock never saw him, and so, day after day the Mouse fared
sumptuously and grew over-bold. But one day, when corn was ripe
and the Cock had been well fed and was settling down to his sitting
nap, the Mouse came out and stole a particularly large piece of
bread, so that in trying to push it into his hole he made some noise
and, moreover, had to stop and tunnel his doorway larger.
The Cock turned his head and looked just as the Mouse was working
his way slowly in, and espied the long, naked tail lying there on the
ground and wriggling as the Mouse moved to and fro at his digging.
“Hah! By the Grandmother of Substance, it is a worm!” cackled the
Cock, and he made one peck at the Mouse’s tail and bit it so hard
that he cut it entirely off and swallowed it at one gulp.
The Mouse, squeaking “Murder!” scurried down into his sleeping-
place, and fell to licking his tail until his chops were all pink and his
mouth was drawn down like a crying woman’s; for he loved his long
tail as a young dancer loves the glory of his long hair, and he cried
continually: “Weh tsu tsu, weh tsu tse, yam hok ti-i-i!” and thought:
“Oh, that shameless great beast! By the Demon of Slave-creatures,
I’ll have my payment of him! For he is worse than an owl or a night-
hawk. They eat us all up, but he has taken away the very mark of
my mousehood and left me to mourn it. I’ll take vengeance on him,
will I!”
So, from that time the Mouse thought how he might compass it, and
this plan seemed best: He would creep out some day, all maimed of
tail as he was, and implore pity, and thus, perchance, make friends
for a while with the Tâkâkâ Cock. So he took seed-down, and made
a plaster of it with nut-resin, and applied it to the stump of his tail.
Then, on a morning, holding his tail up as a dog does his foot when
maimed by a cactus, he crawled to the edge of his hole and cried in
a weak voice to the Tâkâkâ:

“Ani, yoa yoa! Itâ-ak’ya Mosa,

Motcho wak’ya,
Oshe wak’ya,
Ethl hâ asha ni ha. Ha na, yoa, ha na!”

Look you, pity, pity! Master of Food Substance,

Of my maiming,
Of my hunger,
I am all but dying. Ah me, pity, ah me!
Whereupon he held up his tail, which was a safe thing to do, you
see, for it no longer looked like a worm or any other eatable.
Now, the Tâkâkâ was flattered to be called a master of plenty, so he
said, quite haughtily (for he had eaten and could not bend his neck,
and felt proud, withal), “Come in, you poor little thing, and eat all
you want. As if I cared for what the like of you could eat!” So the
Mouse went in and ate very little, as became a polite stranger, and
thanking the Cock, bade him good-day and went back to his hole.
By-and-by he came again, and this time he brought part of a
nutshell containing fine white meat. When he had shouted warning
of his coming and entered the corral cage, he said: “Comrade father,
let us eat together. Of this food I have plenty, gathered from yonder
high nut-tree which I climb every autumn when the corn is ripe and
cut the nuts therefrom. But of all food yours I most relish, since I
cannot store such in my cellar. Now, it may be you will equally relish
mine; so let us eat, then, together.”
“It is well, comrade child,” replied the Cock; so they began to eat.
But the Cock had no sooner tasted the nut than he fairly chuckled
for joy, and having speedily made an end of the kernel, fell to
lamenting his hard lot. “Alas, ah me!” he said. “My grandmother
brings me, on rare days, something like to this, but picked all too
clean. There is nought eatable so nice. Comrade little one, do you
have plenty of this kind, did you say?”
“Oh, yes,” replied the Mouse; “but, you see, the season is near to an
end now, and when I want more nuts I must go and gather them
from the tree. Look, now! Why do you not go there also? That is the
tree, close by.”
“Ah me, I cannot escape, woe to me! Look at my wings,” said the
Cock, “they are worn to bristles—and as to the beard on my breast,
my chief ornament, alas! it is all crumpled and uneven, so much
have I tried to fly out and so hard have I pushed against the bars.
As for the door, my grandmother claps that shut and fastens it
tightly with thongs, be you sure, as soon as ever she finishes the
feeding of me!”
“Ha! ha!” exclaimed the Mouse. “If that’s all, there’s nothing easier
than to open that. Look at my teeth; I even crack the hard nuts with
these scrapers of mine! Wait!” He ran nimbly up the wicket and soon
gnawed through the holding-string. “There! comrade father; push
open the door, you are bigger than I, and we will go nutting.”
“Thanks this day,” cried the Cock, and shoving the wicket open, he
ran forth cackling and crowing for gladness.
Then the Mouse led the way to the tree. Up the trunk he ran, and
climbed and climbed until he came to the topmost boughs. “Ha! the
nuts are fine and ripe up here,” he shouted.
But the Tâkâkâ fluttered and flew all in vain; his wings were so worn
he could not win even to the lowermost branches. “Oh! have pity on
me, comrade child! Cut off some of the nuts and throw them down
to me, do! My wings are so worn I cannot fly any better than the
grandmother’s old dog, who is my neighbor over there.”
“Be patient, be patient, father!” exclaimed the Mouse. “I am cracking
a big one for you as fast as I can. There, catch it!” and he threw a
fat nut close to the Cock, who gleefully devoured the kernel and,
without so much as thanks, called for more.
“Wait, father,” said the Mouse. “There! Stand right under me, so.
Now, catch it; this is a big one!” Saying which the Mouse crawled out
until he was straight over the Cock. “Now, then,” said he, “watch in
front!” and he let fall the nut. It hit the Cock on the head so hard
that it bruised the skin off and stunned the old Tâkâkâ so that he fell
over and died for a short time, utterly forgetting.
“Té mi thlo kô thlo kwa!” shouted the Mouse, as he hurried down
the tree. “A little waiting, and lo! What my foe would do to me, I to
him do, indeed!” Whereupon he ran across, before ever the Cock
had opened an eye, and gnawed his bristles off so short that they
never could grow again. “There, now!” said the Mouse. “Lo! thus
healed is my heart, and my enemy is even as he made me, bereft of
distinction!” Then he ran back to his cellar, satisfied.
Finally the Cock opened his eyes. “Ah me, my head!” he exclaimed.
Then, moaning, he staggered to his feet, and in doing so he espied
the nut. It was smooth and round, like a brown egg. When the Cock
saw it he fell to lamenting more loudly than ever: “Oh, my head! Tâ-
kâ-kâ-kâ-â-â!” But the top of his head kept bleeding and swelling
until it was all covered over with welts of gore, and it grew so heavy,
withal, that the Tâkâkâ thought he would surely die. So off to his
grandmother he went, lamenting all the way.
Hearing him, the grandmother opened the door, and cried: “What
now?”
“Oh, my grandmother, ah me! I am murdered!” he answered. “A
great, round, hard seed was dropped on my head by a little creature
with a short, one-feathered tail, who came and told me that it was
good to eat and—oh! my head is all bleeding and swollen! By the
light of your favor, bind my wound for me lest, alas, I die!”
“Served you right! Why did you leave your place, knowing better?”
cried the old woman. “I will not bind your head unless you give me
your very bristles of manhood, that you may remember your lesson!”
“Oh! take them, grandmother!” cried the Cock; but when he looked
down, alas! the beard of his breast, the glory of his kind, was all
gone. “Ah me! ah me! What shall I do?” he again cried. But the old
woman told him that unless he brought her at least four bristles she
would not cure him, and forthwith she shut the door.
So the poor Cock slowly staggered back toward his corral, hoping to
find some of the hairs that had been gnawed off. As he passed the
little lodge of his neighbor, the Dog, he caught sight of old Wahtsita’s
fine muzzle-beard. “Ha!” thought he. Then he told the Dog his tale,
and begged of him four hairs—“only four!”
“You great, pampered noise-maker, give me some bread, then, fine
bread, and I will give you the hairs.” Whereupon the Cock thought,
and went to the house of a Trader of Foodstuffs; and he told him
also the tale.
“Well, then, bring me some wood with which I may heat the oven to
bake the bread,” said the Trader of Foodstuffs.
The Cock went to some Woods near by. “Oh, ye Beloved of the
Trees, drop me dry branches!” And with this he told the Trees his
tale; but the Trees shook their leaves and said: “No rain has fallen,
and all our branches will soon be dry. Beseech the Waters that they
give us drink, then we will gladly give you wood.”
Then the Cock went to a Spring near by,—and when he saw in it
how his head was swollen and he found that it was growing harder,
he again began to lament.
“What matters?” murmured the Beloved of the Waters.
Then he told them the tale also.
“Listen!” said the Beings of Water. “Long have men neglected their
duties, and the Beloved of the Clouds need payment of due no less
than ourselves, the Trees, the Food-maker, the Dog, and the Old
Woman. Behold! no plumes are set about our border! Now,
therefore, pay to them of thy feathers—four floating plumes from
under thy wings—and set them close over us, that, seen in our
depths from the sky, they will lure the Beloved of the Clouds with
their rain-laden breaths. Thus will our stream-way be replenished
and the Trees watered, and their Winds in the Trees will drop thee
dead branches wherewith thou mayest make payment and all will be
well.”
Forthwith the Tâkâkâ plucked four of his best plumes and set them,
one on the northern, one on the western, one on the southern, and
one on the eastern border of the Pool. Then the Winds of the Four
Quarters began to breathe upon the four plumes, and with those
Breaths of the Beloved came Clouds, and from the Clouds fell Rain,
and the Trees threw down dry branches, and the Wind placed
among them Red-top Grass, which is light and therefore lightens the
load it is among. And when the Cock returned and gathered a little
bundle of fagots, lo! the Red-top made it so light that he easily
carried it to the Food-maker, who gave him bread, for which the Dog
gave him four bristles, and these he took to the old Grandmother.
“Ha!” exclaimed she. “Now, child, I will cure thee, but thou hast
been so long that thy head will always be welted and covered with
proud-flesh, even though healed. Still, it must ever be so. Doing
right keeps right; doing wrong makes wrong, which, to make right,
one must even pay as the sick pay those who cure them. Go now,
and bide whither I bid thee.”
When, after a time, the Cock became well, lo! there were great,
flabby, blood-red welts on his head and blue marks on his temples
where they were bruised so sore. Now, listen:
It is for this reason that ever since that time the medicine masters of
that people never give cure without pay; never, for there is no virtue
in medicine of no value. Ever since then cocks have had no bristles
on their breasts—only little humps where they ought to be;—and
they always have blood-red crests of meat on their heads. And even
when a hen lays an egg and a tâkâkâ cock sees it, he begins to tâ-
kâ-kâ-â as the ancient of them all did when he saw the brown nut.
And sometimes they even pick at and eat these seeds of their own
children, especially when they are cracked.
As for mice, we know how they went into the meal-bags in olden
times and came out something else, and, getting smoked, became
tsothliko-ahâi, with long, bare tails. But that was before the Cock cut
the tail of the tsothliko Mouse off. Ever since he cried in agony:
“Weh tsu yii weh tsu!” like a child with a burnt finger, his children
have been called Wehtsutsukwe, and wander wild in the fields;
hence field-mice to this day have short tails, brown-stained and
hairy; and their chops are all pink, and when you look them in the
face they seem always to be crying.
Thus shortens my story.
 THE GIANT CLOUD-SWALLOWER
A TALE OF CAÑON DE CHELLY

Translator’s Introduction

D
EEP down in cañons of the Southwest, especially where
they are joined by other cañons, the traveller may see
standing forth from or hugging the angles of the cliffs,
great towering needles of stone—weird, rugged, fantastic,
oftentimes single, as often—like gigantic wind-stripped trees with
lesser trees standing beside them—double or treble. Seen
suddenly at a turn in the cañon these giant stones startle the
gazer with their monstrous and human proportions, like giants,
indeed, at bay against the sheer rock walls, protecting their
young, who appear anon to crouch at the knees of their fathers
or cling to their sides.
Few white men behold these statuesque stones in the moonlight,
or in the gray light and white mists of the morning. At midday
they seem dead or asleep while standing; but when the moon is
shining above them and the wanderer below looks up to them,
lo! the moon stands still and these mighty crags start forth,
advancing noiselessly. His back is frozen, and even in the yielding
sand his feet are held fast by terror—a delicious, ghostly terror,
withal! Still he gazes fascinated, and as the shadow of the
moonlight falls toward him over the topmost crest, lo, again! its
crown is illumined and circled as if by a halo of snow-light, and
back and forth from this luminous fillet over that high stony brow,
black hair seems to tumble and gather.
 Again, beheld in the dawn-light, when the mists are rising slowly
and are waving to and fro around the giddy columns, hiding the
cliffs behind them, these vast pinnacles seem to nod and to
waver or to sway themselves backward and forward, all as
silently as before. Soon, when the sun is risen and the mists from
below fade away, the wind blows more mist from the mesa; you
see clouds of it pour from the cliff edge, just behind and above
these great towers, and shimmer against the bright sky; but as
soon as these clouds pass the crag-nests they are lost in the
sunlight around them—lost so fast, as yet others come on, that
the stone giants seem to drink them.
Of such rocks, according to their variety and local surroundings,
the Zuñis relate many tales which are so ingenious and befitting
that if we believed, as the Zuñis do, that in the time of creation
when all things were young and soft and were therefore easily
fashioned by whatever chanced to befall them—into this thing or
that thing, into this plant or that plant, this animal or that, and so
on endlessly through a dramatic story longer than Shakespeare
or the Bible—we would fain believe also as he does in the quaint
incidents of these stories of the time when all things were new
and the world was becoming as we see it now.
One of these tales, a variant of others pertaining to particular
standing rocks in the west, south, or east, is told of that wonder
to all beholders, “El Capitan,” of the Cañon de Chelly in the north.
No one who has seen this stupendous rock column can fail to be
interested in the following legend, or will fail to realize how, as
this introduction endeavors to make plainer, the Zuñi poet and
philosopher of olden times built up a story which he verily
believed quite sufficient to account for the great shaft of
sandstone and its many details and surroundings.—F. H. C.
Häki Suto, or Foretop Knot, he whose hair was done up over his
forehead like a quail’s crest, lived among the great cliffs of the north
long ago, when the world was new. He was a giant, so tall that men
called him Lo Ikwithltchunona, or the Cloud-swallower. A devourer of
men was he,—men were his meat—yea, and a drinker of their very
substance was he, for the cloud-breaths of the beloved gods, and
souls of the dead, whence descend rains, even these were his drink.
Wherefore the People of the Cliffs sought to slay him, and hero after
hero perished thuswise. Wherefore, too, snow ceased in the north
and the west; rain ceased in the south and the east; the mists of the
mountains above were drunk up; the waters of the valleys below
were dried up; corn withered in the fields; men hungered and died in
the cliffs.
Then came the Twin Gods of War, Áhaiyúta and Mátsailéma, who in
play staked the lives of foes and fierce creatures. “Lo! it is not well
with our children, men,” said they. “Let us destroy this Häki Suto, the
swallower of clouds,” said they.
They were walking along the trail which leads southward to the
Smooth-rocks-descending.
“O, grandchildren, where be ye wending?” said a little, little quavering
voice. They looked,—the younger, then the elder. There on the tip of
a grass-stalk, waving her banner of down-stuff, stood their
grandmother, Spinner of Meshes.
“The Spider! Our Grandmother Spider!” cried one of the gods to the
other. “Ho! grandmother, was that you calling?” shouted they to her.
“Yea, children; where wend ye this noon-day?”
“A-warring we are going,” said they. “Look now!

“No beads for to broider your awning

Have fallen this many a morning.”

“Aha, wait ye! Whom ye seek, verily I know him well,” said the
Spider-woman.
 “Like a tree fallen down from the mountain
He lies by the side of the cliff-trail
And feigns to sleep there, yet is wary.
I will sew up his eyes with my down-cords.
Then come ye and smite him, grandchildren.”

She ran ahead. There lay Häki Suto, his legs over the trail where men
journeyed. Great, like the trunks and branches of pine trees cast
down by a wind-storm, were his legs arching over the pathway, and
when some one chanced to come by, the giant would call out: “Good
morning!” and bid him “pass right along under.” “I am old and
rheumatic,” he would continue, oh, so politely! “Do not mind my
rudeness, therefore; run right along under; never fear, run right along
under!” But when the hunter tried to pass, kúutsu! Häki Suto would
snatch him up and cast him over the cliff to be eaten by the young
Forehead-cresters.
The Spider stepped never so lightly, and climbed up behind his great
ear, and then busily wove at her web, to and fro, up and down, and
in and out of his eyelashes she busily plied at her web.
“Pesk the birds and buzz creatures!” growled the giant, twitching this
way and that his eyebrows, which tickled; but he would not stir,—for
he heard the War-gods coming, and thought them fat hunters and
needs must feign sleepy.
And these? Ha! ha! They begin to sing, as was their fearless wont
sometimes. Häki Suto never looked, but yawned and drawled as they
came near, and nearer. “Never mind, my children, pass right along
under, pass right along under; I am lame and tired this morning,” said
he.
Áhaiyúta ran to the left. Mátsailéma ran to the right. Häki Suto sprang
up to catch them, but his eyes were so blinded with cobwebs that he
missed them and feigned to fall, crying: “Ouch! my poor back! my
poor back! Pass right along under, my children, it was only a crick in
my back. Ouch! Oh, my poor back!” But they whacked him over the
head and stomach till he stiffened and died. Then shouting “So ho!”
they shoved him over the cliff.
The Navahos say that the grandmother tied him there by the hair—by
his top-knot—where you see the white streaks on the pillar, so they
say; but it’s the birds that streak the pillar, and this is the way. When
Häki Suto fell, his feet drave far into the sands, and the Storm-gods
rushed in to the aid of their children, the War-gods, and drifted his
blood-bedrenched carcass all over with sand, whence he dried and
hardened to stone. When the young ones saw him falling, they
forthwith flocked up to devour him, making loud clamor. But the
Twain, seeing this, made after them too and twisted the necks of all
save only the tallest (who was caught in the sands with his father)
and flung them aloft to the winds, whereby one became instantly the
Owl, who twists her head wholly around whensoever she pleases,
and stares as though frightened and strangled; and another the
Falcon became, who perches and nests to this day on the crest of his
sand-covered father, the Giant Cloud-drinker. And the Falcons cry ever
and ever “’Tis father; O father!” (“Tí-tätchu ya-tätchu.”)
But, fearing that never again would the waters refreshen their
cañons, our ancients who dwelt in the cliffs fled away to the
southward and eastward—all save those who had perished aforetime;
they are dead in their homes in the cliff-towns, dried, like their corn-
stalks that died when the rain stopped long, long ago, when all things
were new.
Thus shortens my story.
Photo by A. C. Vroman
ZUÑI WOMEN CARRYING WATER
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