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Medical Epigenetics

Second Edition
 Translational Epigenetics Series
Trygve Tollefsbol - Series Editor
Transgenerational Epigenetics
Edited by Trygve O. Tollefsbol, 2014
Personalized Epigenetics
Edited by Trygve O. Tollefsbol, 2015
Epigenetic Technological Applications
Edited by Y. George Zheng, 2015
Epigenetic Cancer Therapy
Edited by Steven G. Gray, 2015
DNA Methylation and Complex Human Disease
By Michel Neidhart, 2015
Epigenomics in Health and Disease
Edited by Mario F. Fraga and Agustin F. Fernández, 2015
Epigenetic Gene Expression and Regulation
Edited by Suming Huang, Michael Litt and C. Ann
Blakey, 2015
Epigenetic Biomarkers and Diagnostics
Edited by Jose Luis García-Giménez, 2015
Drug Discovery in Cancer Epigenetics
Edited by Gerda Egger and Paola Barbara Arimondo,
2015
Medical Epigenetics
Edited by Trygve O. Tollefsbol, 2016
Chromatin Signaling and Diseases
Edited by Olivier Binda and Martin Fernandez-Zapico,
2016
Genome Stability
Edited by Igor Kovalchuk and Olga Kovalchuk, 2016
Chromatin Regulation and Dynamics
Edited by Anita Göndör, 2016
Neuropsychiatric Disorders and Epigenetics
Edited by Dag H. Yasui, Jacob Peedicayil and Dennis R.
Grayson, 2016
Polycomb Group Proteins
Edited by Vincenzo Pirrotta, 2016
Epigenetics and Systems Biology
Edited by Leonie Ringrose, 2017
Cancer and Noncoding RNAs
Edited by Jayprokas Chakrabarti and Sanga Mitra,
2017
Nuclear Architecture and Dynamics
Edited by Christophe Lavelle and Jean-Marc Victor, 2017
Epigenetic Mechanisms in Cancer
Edited by Sabita Saldanha, 2017
Epigenetics of Aging and Longevity
Edited by Alexey Moskalev and Alexander M. Vaiserman,
2017
The Epigenetics of Autoimmunity
Edited by Rongxin Zhang, 2018
Epigenetics in Human Disease, Second Edition
Edited by Trygve O. Tollefsbol, 2018
Epigenetics of Chronic Pain
Edited by Guang Bai and Ke Ren, 2018
Epigenetics of Cancer Prevention
Edited by Anupam Bishayee and Deepak Bhatia, 2018
Computational Epigenetics and Diseases
Edited by Loo Keat Wei, 2019
Pharmacoepigenetics
Edited by Ramón Cacabelos, 2019
Epigenetics and Regeneration
Edited by Daniela Palacios, 2019
Chromatin Signaling and Neurological Disorders
Edited by Olivier Binda, 2019
Transgenerational Epigenetics, Second Edition
Edited by Trygve Tollefsbol, 2019
Nutritional Epigenomics
Edited by Bradley Ferguson, 2019
Prognostic Epigenetics
Edited by Shilpy Sharma, 2019
Epigenetics of the Immune System
Edited by Dieter Kabelitz, 2020
Stem Cell Epigenetics
Edited by Eran Meshorer and Giuseppe Testa, 2020
Epigenetics Methods
Edited by Trygve Tollefsbol, 2020
Histone Modifications in Therapy
Edited by Pedro Castelo-Branco and Carmen Jeronimo,
2020
Environmental Epigenetics in Toxicology and Public Health
Edited by Rebecca Fry, 2020
Developmental Human Behavioral Epigenetics
Edited by Livio Provenzi and Rosario Montirosso, 2020
Epigenetics in Cardiovascular Disease
Edited by Yvan Devaux and Emma Robinson, 2021
Epigenetics of Exercise and Sports
Edited by Stuart M. Raleigh, 2021
Genome Stability, Second Edition
Edited by Igor Kovulchuk and Olga Kovulchuk, 2021
Twin and Family Studies of Epigenetics
Edited by Shuai Li and John L. Hopper, 2021
Epigenetics and Metabolomics
Edited by Paban K. Agrawala and Poonam Rana, 2021
Translational Epigenetics Series
Medical Epigenetics
Second Edition
Volume 29

Edited by

Trygve O. Tollefsbol
Distinguished Professor of Biology, Senior Scientist, Comprehensive Cancer Center, Comprehensive
Center for Healthy Aging, University of Alabama at Birmingham, AL, United States
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Contents

Contributors xvii Infection 23

Preface xxi Conclusions and perspectives 23
Acknowledgment 25
Abbreviations 25
Section A References 26
Overview
3. Lifestyle and preventive medical
1. Advances in medical epigenetics epigenetics
Trygve O. Tollefsbol Kamaldeen Olalekan Sanusi, Yaaqub Abiodun
Uthman, Der Jiun Ooi, Maznah Ismail, and
Introduction 3 Mustapha Umar Imam
Basic principles of epigenetics 3
General medical aspects of epigenetics 4 Introduction 33
Epigenetics of system disorders 4 Epigenetics 33
Multisystem medical epigenetics 5 How epigenetics influence risk of diseases 33
Bioinformatics of epigenetic medicine 5 How lifestyle determines epigenetics 34
Pharmacology of epigenetics 6 How knowledge on epigenetics could be
Therapeutic epigenetics 6 used to prevent diseases 34
Medical epigenetics: Future prospects 7 Impact of dietary pattern on the epigenome 35
Conclusion 7 Carbohydrates and epigenetic modifications 35
References 8 Proteins and epigenetic modifications 36
Fatty acids and epigenetic modifications 37
Role of micronutrients in epigenetics 37
Section B Bioactive compounds 38
General medical aspects Exercise and epigenetics 39
Environmental factors and epigenetic
of epigenetics modification 41
Lifestyle modification as a preventive tool
2. Environmental epigenetic for medical epigenetics 41
epidemiology Conclusion 43
Alexander Vaiserman, Oleh Lushchak, and References 43
Alexander Koliada
Introduction 11 4. Environmental medical
Malnutrition 11 epigenetics: A review of
Environmental pollutants 13 epigenetically induced medical
Air pollution 13 risks generated from exposures in
Endocrine-disrupting chemicals 16 our air, food, and personal products
Heavy metals 16
Rachel L. Miller and Jessica Oh
Substance abuse 18
Alcohol 18 Introduction 51
Tobacco smoking 19 Allergens 51
Marijuana smoking 20 Aeroallergens 51
Opioids 20 Food allergens 53

v
vi  Contents

Secondhand cigarette smoke and vaping 53 Interconnectivity of the neurotransmitter

Traffic-related air pollution 55 systems 88
PM2.5 56 The dopaminergic system 89
Diesel exhaust particles 56 Behavioral disorders associated with the
Polycyclic aromatic hydrocarbons 57 dopaminergic system 90
Trace metals 58 Evidence for glucocorticoid effect on
Heavy metals 58 dopaminergic transmission 90
Chromium 58 Glucocorticoids and dopamine in drug
Arsenic 58 addiction 90
Lead 59 Epigenetic mediators of glucocorticoids on
Cadmium 60 dopamine-related behavior 91
Endocrine-disrupting chemicals 60 Adrenergic and noradrenergic systems 92
Bisphenol A 60 Behavioral disorders associated with the
Phthalates 62 adrenergic and noradrenergic system 92
Parabens 63 Evidence for glucocorticoid effect on
Flame retardants/polybrominated adrenergic and noradrenergic
diphenyl ethers 63 transmission 92
Pesticides and fungicides 63 Epigenetic mediators of glucocorticoids on
Vinclozolin 63 adrenaline- and noradrenaline-related
Persistent organic pollutants and other behavior 93
pesticides 64 The serotonergic (5-HT) system 93
Volatile organic compounds 65 Behavioral disorders associated with the
Farm exposure 65 serotonergic system 93
Diet 66 Evidence for glucocorticoid effect on
Folic acid and other methyl donors 66 serotonergic transmission 93
Additional vitamin and antioxidant Epigenetic mediators of glucocorticoids on
supplementation 67 serotonin-related behavior 94
Dietary fat, sucrose 67 Glutamate and GABA systems 94
Famine 68 Behavioral disorders associated with the
Conclusions/outstanding questions 69 glutamate and GABA system 94
Abbreviations 72 Evidence for glucocorticoid effect on
Glossary 73 glutamate and GABA system 95
References 73 Epigenetic mediators of glucocorticoids on
glutamate and GABA-related behavior 95
5. Behavioral medical epigenetics Conclusion 95
References 96
O.H. Cox and R.S. Lee
Introduction 81 6. Medical epigenetics and twins
Impact of environmental factors on behavior 81
J.C. Eissenberg
Animal models and studies of human behavior 82
Environmental stressors and epigenetic Introduction 103
mediators of the stress response 82 Monogenic disorders: Twin studies and the
Nonepigenetic and alternate mechanisms epigenetics of imprinting disorders 104
of stress 83 Twin studies and Beckwith–Wiedemann
The HPA axis and the stress response 83 syndrome 104
Glucocorticoid signaling and epigenetics 84 Twin studies and Silver–Russell syndrome 105
HPA axis genes: Genes that regulate Twin studies and the epigenetics of
glucocorticoid signaling 85 multifactorial disorders 106
Chronic stress and glucocorticoid resistance 85 Twin studies and the epigenetics of
Glucocorticoid resistance and epigenetics 86 cardiovascular diseases 106
HPA axis genes: Genes that regulate Twin studies and the epigenetics of
tissue-specific processes 87 psychiatric disorders 106
Environmental stressors and Twin studies and the epigenetics of
neurotransmitters 88 aging 108
 Contents  vii

Twin studies and the epigenetics The future 161

of metabolic traits and disease 108 Conflict of interest statement 162
Twin studies and epigenetic mechanisms 109 References 162
Caveats 110
Future directions 111
Conclusions 111 Section C
References 112
Epigenetics of system disorders
7. Epigenetic biomarkers of disease 9. Autoimmune disease and epigenetics
Patricia Chaves, Juan Luis Onieva, and Sarah J. Blossom
Isabel Barragán
Autoimmune disease overview 171
Introduction 117 Autoimmune disease etiology 171
Epigenetic biomarkers 117 Epigenetics and autoimmunity 172
Disruption of the “epigenetic machinery” Epigenetic regulation of T cell subset
in cancer 117 differentiation 172
Epigenetic mechanisms of acquired drug DNA methylation and autoimmune disease 173
resistance 118 Histone modifications and autoimmune
Types of epigenetic modifications 118 disease 174
Epigenetic biomarkers in cancer 119 RNA modifications in autoimmune disease 175
Diagnosis, prognosis, and drug response Environmental epigenetics 176
epigenetic biomarkers in solid biopsies 119 Environmental epigenetics and
Diagnosis, prognosis, and drug response autoimmunity 176
biomarkers in liquid biopsies 121 Xenobiotic-induced epigenetic changes
Methods for assessing epigenetic changes for and autoimmunity 176
biomarkers 124 Trichloroethylene 176
Genome-wide epigenetic analysis 126 Trichloroethylene-mediated immunotoxicity 177
Locus-specific epigenetic analysis 127 Trichloroethylene and autoimmunity 177
Specific methods for liquid biopsy 128 Trichloroethylene-induced autoimmunity
Bioinformatic analysis 129 in experimental models 177
Clinical application of epigenetic biomarkers 129 Trichloroethylene-mediated epigenetic
Epigenetic biomarkers in precision medicine 129 changes in CD4+ T cells 177
Epigenetic plasticity as a therapeutic target 133 Conclusions 178
Epigenomic modulation drugs 133 References 178
Future perspectives 134
Conclusion 135
Abbreviations 135
10. Epigenetics of pulmonary diseases
References 136 Akshaya Thoutam and Narasaiah Kolliputi
Introduction 185
8. Prognostic epigenetics Epigenetic basics 185
Epigenetics in disease 186
Adriana Fodor, Adriana Rusu, Gabriela Roman,
Epigenetics in the lungs 188
Ramona Suharoschi, Romana Vulturar,
Epigenetics in pulmonary diseases 190
Adela Sitar-Taut, and Angela Cozma
Lung cancer 190
Introduction 143 Pulmonary hypertension 191
DNA methylation markers of cancer Chronic obstructive pulmonary disease 192
prognosis 143 Idiopathic pulmonary fibrosis 193
Histone modifications as markers of cancer Tuberculosis 193
prognosis 153 Conclusion 194
Noncoding RNA prognostic markers in Grants 194
cancer 156 Disclosures 194
Prognostic epigenetic markers in Author contributions 194
nonmalignant pathology 158 References 194
viii  Contents

11. Cardiovascular disorders and Epigenetics in dermatomyositis 236

epigenetics Epigenetics in atopic dermatitis 237
Infectious skin diseases 238
Charbel Abi Khalil Introduction 238
Introduction 197 Epigenetics in HSV infection 238
Early heart development and the fetal Epigenetics in HPV infection 239
origin of cardiovascular disease 197 Skin tumors 239
Epigenetic involvement in cardiovascular Introduction 239
risk factors 198 Epigenetics in melanoma 240
Smoking 198 Epigenetics in cutaneous T-cell lymphoma 242
Age 199 Skin aging 243
Hypertension 199 Introduction 243
Obesity and dyslipidemia 199 Epigenetic changes of skin 243
Diabetes 200 Epigenetic therapeutics for aged skin 244
Epigenetics and cardiovascular disease 202 Conclusions 244
Endothelial dysfunction and atherosclerosis 202 Abbreviations 244
Ischemic heart disease 203 Acknowledgments 245
Stroke 204 References 245
Vascular disease 204
Cardiac hypertrophy 204 14. Epigenetics in bone and joint
Heart failure 205 disorders
Epigenetic-based cardiovascular therapy 206 N. Altorok, V. Nagaraja, and B. Kahaleh
Conclusion 206
References 207 Introduction 251
Epigenetic regulation of the immune
12. Epigenomics of intestinal disease system in rheumatic diseases 251
Systemic lupus erythematosus 253
S. Hashimoto-Hill, D.R. Kelly, and T. Alenghat Systemic sclerosis 256
Introduction 213 Rheumatoid arthritis 259
Epigenetics and intestinal development 214 Sjögren syndrome 262
Intestinal homeostasis and the microbiota 215 Osteoarthritis 264
Epigenetics, intestinal homeostasis, Osteoporosis 265
and the microbiota 216 Psoriasis 267
Microbiota-derived metabolites 217 DNA methylation aberrancies and psoriasis 267
Diet and the intestinal epigenome 219 Vasculitis 268
Colon cancer 220 Epigenetics therapy in rheumatic diseases 269
Inflammatory bowel disease 221 Epigenetic therapeutics for SLE 269
Irritable bowel syndrome 223 Epigenetic therapeutics for rheumatoid
Celiac disease 224 arthritis 269
Therapeutics 224 Epigenetic therapeutics for systemic
Future directions 225 sclerosis 270
Glossary 225 miRNAs as biomarkers for rheumatology
Acknowledgments 226 and bone diseases 270
References 226 Conclusions 271
References 271
13. Epigenetics of skin disorders
15. Epigenetics of muscle disorders
Shuaihantian Luo and Qianjin Lu
Elisa Oltra
Immunologic skin diseases 231
Introduction 231 Introduction 279
Epigenetics in systemic lupus Atrial fibrillation 279
erythematosus 231 Pathophysiology, demographics, diagnosis,
Epigenetics in psoriasis 234 and treatment options of AF 279
Epigenetics in vitiligo 236 Genetic determinants of AF 280
 Contents  ix

Epigenetic determinants of AF 281 Intraocular tumors 360

Limitations and prospective challenges Discussion and conclusions 362
of AF epigenetic studies 288 Conflict of interest 363
Fibromyalgia 288 References 363
Pathophysiology, demographics, diagnosis,
and treatment options of FM 288
Genetic determinants of FM 289 Section D
Epigenetic determinants of FM 289 Multi-system medical epigenetics
Limitations and prospective challenges
of FM epigenetic studies 293 18. Pediatric diseases and epigenetics
Gastrointestinal disorders 293
J.G. Hall and R. Weksberg
Pathophysiology, demographics, diagnosis,
and treatment options of GI 293 Introduction 377
Genetic determinants of GI 295 Specific syndromes and disorders whose
Epigenetic determinants of GI 295 genes are involved in the processes and
Limitations and prospective challenges mechanisms of epigenetic regulation of
of GI epigenetic studies 297 gene expression 377
Abbreviations 298 Rett syndrome (reader) 385
References 298 Alpha thalassemia/mental retardation
syndrome X-linked syndrome (remodeler) 385
16. Reproductive disease epigenetics ICF syndrome (writer) 385
Rubinstein–Taybi syndrome (writer) 386
Maricarmen Colon-Diaz, Alexander J. Jaramillo,
Floating–Harbor syndrome (remodeler) 386
Edwin Y. Soto, and Perla M. Elosegui
Microdeletions and duplications of
Introduction 309 chromosomes 386
Gametogenesis 309 Disorders of genomic imprinting 387
Spermatogenesis 309 Descriptions of particularly well-known
Oogenesis 311 syndromes involving parental imprinting 387
Male reproductive disorders 312 Prader–Willi syndrome 387
Male infertility 312 Angelman syndrome 388
Testicular cancer 315 Beckwith–Wiedemann syndrome (aka
Female reproductive disorders 316 Wiedemann–Beckwith syndrome) 388
Female infertility 316 Russell–Silver syndrome (aka Silver–Russell
Endometrial disorders 317 syndrome) 389
Ovarian disorders 323 Molecular diagnosis for epigenetic
Placental syndromes 327 disorders 389
Preeclampsia 327 Known environmental exposures which are
Intrauterine growth restriction (idiopathic) 330 likely to have disturbances in epigenetic
Hydatidiform mole 331 regulation 390
Human papillomavirus and cervical cancer 332 Teratogens 390
Summary 334 Endocrine disruptors 390
References 334 Folic acid 390
Developmental disorders that are likely
17. Epigenetics in ocular medicine to involve epigenetic mechanisms 392
Intellectual disability 392
Ji Liu
Autism spectrum disorders 392
Introduction 347 Other pediatric disorders 392
Epigenetics and the eye 347 Human malformations (birth defects) 392
Epigenetics in ocular disease 348 Monozygotic twins 393
Myopia 348 Preconception and periconception
Anterior segment diseases 349 effects 393
Glaucoma 352 Microbiome 393
Vitreoretinal diseases 354 Developmental origins of health
Uveitis 359 and disease (DOHaD) 394
x  Contents

The application of epigenetic research to 21. Epigenetics in acute myeloid

public health policy of the future 396 leukemia
Not overfeeding IUGR infants 396
Placental dimensions predict prenatal Carmela Dell’Aversana, Cristina Giorgio,
predisposition to chronic disease 396 Francesco Paolo Tambaro, Giulia Sgueglia,
A new type of family history 396 and Lucia Altucci
The future impact of epigenetics on pediatrics 396 Introduction 447
Acknowledgments 397 Epigenetic regulation of the genome 447
Abbreviations 397 Normal hematopoiesis 447
References 397 Acute myeloid leukemia 448
Environment 448
19. Epigenetics of infectious diseases Genetic and cytogenetic anomalies 449
K.L. Seib and M.P. Jennings Epigenetics in acute myeloid leukemia 450
DNA methylation and AML 451
Introduction 407 DNA hydroxymethylation and AML 451
Pathogen-induced epigenetic modifications Alterations of histone-targeting players
in host cells 408 in AML 452
DNA methylation 408 Noncoding RNA deregulation in AML 454
Helicobacter pylori and altered DNA Epigenetic-based therapy 456
methylation in infection and gastric cancer 410 DNMT inhibitors 456
Histone modifications 411 HDAC inhibitors 458
Epigenetic modifications in bacterial pathogens 412 HMT inhibitors 460
Methylation of DNA in bacterial pathogens 412 HDM inhibitors 461
The Dam N6-Adenine DNA methyltransferase 414 IDH1/2 inhibitors 461
Phasevarions—Phase-variable DNA Conclusions 462
methyltransferases controlling global References 462
gene expression 415
Conclusions 418
Glossary 418 22. Epigenetic regulation in cancer
Abbreviations 419 metastasis
Acknowledgments 419
Guanying Bianca Xu, Huan Wang,
References 419
Shijia Alexia Chen, and Hong Chen
20. Clinical utility of solid tumor Overview of cancer metastasis 471
epigenetics Epigenetic control 472
Molecular pathways of EMT 473
Engin Demirdizen, Julian Taranda, and
DNA methylation and EMT 474
Sevin Turcan
Histone modification and EMT 474
Epigenetic drugs 425 MicroRNA regulation of EMT 475
Combination epigenetic therapy 428 Long noncoding RNA (lncRNA)
Epigenetics and immunity 432 regulation of EMT 476
Challenges 433 Anoikis resistance 476
DNA-methylation-based classification Epigenetic regulations of apoptosis through
of tumors 433 FLIP and caspase-8 477
Liquid biopsy 435 Anchorage-independent growth 477
Tumor-associated features in blood 436 Extravasation and colonization 479
Blood- and cancer-specific DNA Epigenome-wide big data analysis for
methylation patterns 436 mechanistic understanding of
Mapping nucleosome positions 437 metastasis 480
Liquid biopsies for solid tumors in RNA-seq 480
clinical care 437 ChIP-seq 481
Concluding remarks 438 MeDIP-seq 482
Acknowledgments 438 scRNA-seq 482
Abbreviations 439 Abbreviations 483
References 440 References 483
 Contents  xi

23. Epigenetics in exercise science Opportunities in preclinical safety

and sports medicine assessment 545
Potential tools for screening of
A. Schenk, S. Proschinger, and P. Zimmer epigenetic effects 546
Introduction 491 Conclusion and future perspective 549
General findings 491 Disclaimer 550
Muscle tissue 492 Abbreviations 550
Blood cells 496 References 553
Cardiovascular tissues 498
Brain 500 26. Pharmacoepigenomics in
Other tissues 502
neurodegenerative diseases
Conclusion 503
Acknowledgments 503 Nicoletta Nuzziello and Maria Liguori
Abbreviations 503
Introduction 559
References 504
NDD-specific pharmacoepigenomic
signatures 560
DNA methylation as a pharmacoepigenomic
Section E target for NDDs 563
Bioinformatics of epigenetic medicine Histone posttranslational modifications
affecting chromatin remodeling as
24. Machine learning in epigenetic diseases pharmacoepigenomic targets for NDDs 565
MiRNAs as pharmacoepigenomic targets
Karyn G. Robinson and Robert E. Akins for NDDs 565
Introduction 513 Epigenetic-modifying drugs for NDDs 568
Fundamentals of machine learning 513 Potential epidrugs targeting DNA
Machine learning applications in epigenetics 517 methylation 568
Performance and limitations of machine Targeting histone modifications for
learning approaches 521 therapeutic purposes 571
Summary 524 Potential epidrugs targeting miRNAs 572
References 524 Epigenetic regulation of pharmacokinetics
and pharmacodynamics 573
Epigenomics in regulating drug
ADME genes 575
Section F Conclusion 576
Pharmacology of epigenetics References 576

25. Epigenetics in toxicology and drug

development
Section G
J. Tajbakhsh and J. Singh Therapeutic epigenetics
Introduction 529
Epigenetics and diseases 531 27. Therapeutics and DNA
Aberrant epigenetic features and methylation inhibitors
mechanisms 531
Shyamala C. Navada
Cancer 533
Other complex human diseases 537 Introduction 585
Microbiota 538 Mechanism of action 585
Environmental etiology and influence 539 Application of DNMT inhibitors 586
Considerations in pharmacology and Benign hematology 586
toxicology 541 Myelodysplastic syndromes 587
Role of epigenetics in drug-related Acute myeloid leukemia 589
toxicology 541 Hypomethylating agent combinations
Pharmaceutical exploitation of epigenetic in AML 590
readers 544 Chronic myeloid leukemia 590
xii  Contents

Solid tumors 590 HDAC inhibitors for the treatment of

Epigenetic agents in combination—DNMT diabetes mellitus 617
and HDAC inhibitors 591 Effects of HDAC inhibitors on the
Other DNMT inhibitors 591 pancreatic β-cells in diabetes 617
Novel nucleoside DNMT inhibitors 591 Effects of HDAC inhibitors in diabetic
Orally available 5-aza and 5-azadC 592 kidneys 618
Nonnucleoside DNMT inhibitors 592 Safety issues with the use of HDAC inhibitors 619
Conclusions 592 Conclusions 619
References 593 Abbreviations 620
References 621
28. Histone deacetylase inhibitors in
medical therapeutics 29. Sirtuins as NAD+-dependent
P. Chun deacetylases and their potential in
medical therapy
Introduction 597
Classification of histone deacetylases 597 Ashok Kumar and Mona Dvir-Ginzberg
Classification of HDAC inhibitors 598
Introduction 633
HDAC inhibitors for the treatment of cancer 599
Sirtuins 633
HDACs and cancer 599
Sirtuin activity and function 634
Role of HDAC inhibitors in cancer 599
Chemical reaction and structural insight 637
HDAC inhibitors and clinical outcomes 601
NAD+ cofactor 637
Combination therapy with immune
Modulators of sirtuin activity 642
checkpoint inhibitors 603
Sirtuins as potential therapeutic targets
Conclusions 605
in disease 644
HDAC inhibitors for the treatment of heart
Summary 653
diseases 605
Abbreviations 655
Effects of HDAC inhibition on cardiac
Acknowledgments 656
hypertrophy 606
Conflict of interest 656
Effects of HDAC inhibition on cardiac
References 656
hypertension 608
Effects of HDAC inhibition on myocardial
infarction 608 30. Experimental approaches
Effects of HDAC inhibition on heart failure 609 toward histone acetyltransferase
Effects of HDAC inhibition on atrial modulators as therapeutics
fibrillation 609
D. Chen, H. Wapenaar, and F.J. Dekker
HDAC inhibitors for the treatment
of kidney disease 609 Introduction 665
Effects of HDAC inhibition on renal fibrosis 609 The "histone code" 665
Effects of HDAC inhibitors on renal Histone acetylation 665
inflammation 610 Histone acetyltransferases 666
HDAC inhibitors for the treatment of HAT function 667
idiopathic pulmonary fibrosis 610 HATs in disease 672
HDAC inhibitors for the treatment of Cancer 673
inflammatory bowel disease 612 Inflammatory diseases 674
HDAC inhibitors for the treatment of Neurological disorders 675
rheumatoid arthritis 613 Viral infections 676
HDAC inhibitors for the treatment of HAT modulators 676
schizophrenia 615 Bisubstrate inhibitors 677
HDAC inhibitors for the treatment of Natural products and derivatives 677
Parkinson’s disease 616 Other small-molecule inhibitors 677
Suppression of nuclear α-synuclein 616 Bromodomain inhibitors and other HAT
Inhibition of neuroinflammation and protein inhibitors 679
oxidative stress 616 PROTACs for HATs 680
Increase in GDNF and BDNF 617 HAT activators 681
 Contents  xiii

Challenges in the development of HAT ncRNA as biomarkers of human disorders 723

modulators 682 Cardiovascular disease 724
Therapeutic possibilities of HAT modulators 683 Autoimmune and other inflammatory
HAT modulators in cancers 683 diseases 724
HAT modulators in inflammatory diseases Nervous system disorders 726
and neurological diseases 683 Cancer 727
Conclusion 684 Therapeutic potential of miRNA 728
References 684 Central nervous system 730
Cancer 730
Delivery methods 731
31. Histone methylation modifiers in
siRNAs and saRNAs in clinical trials 731
medical therapeutics Concluding remarks 732
P. Trojer References 732
Introduction 693
33. Nutrients and phytonutrients as
Enhancer of zeste homolog 2 (EZH2, KMT6A) 697
promising epigenetic nutraceuticals
EZH2 functions in transcriptional repression 697
Discovery of EZH2 inhibitors 699 Anait S. Levenson
Therapeutic application of EZH2
Abbreviations 741
inhibitors in NHL 699
Introduction 750
Therapeutic application of EZH2
Epigenetic mechanisms 750
inhibitors in other cancer types 700
Nutrients, phytonutrients, and epigenetics 751
Disruptor of telomeric silencing like
Dietary phytochemicals and nutrients as
(DOT1L, KMT4) 702
modulators of DNA methylation and
DOT1L functions in transcription elongation 702
histone modifications 751
Discovery of DOT1L inhibitors 704
Apigenin 753
Therapeutic application of DOT1L
Curcumin 753
inhibitors in AML 704
Epigallocatechin-3-gallate 766
Lysine-specific demethylase 1 (LSD1, KDM1A) 705
Folate (vitamin B9) 767
LSD1 functions in activation and repression
Genistein 768
of transcription 705
Isothiocyanates 769
Discovery of LSD1 inhibitors 707
Indoles 769
Therapeutic application of LSD1
Lycopene 769
inhibitors in AML and MPNs 707
Organosulfur compounds 770
Therapeutic application of LSD1
Polyunsaturated fatty acids 770
inhibitors in solid tumors 708
Quercetin 770
Targeting other histone methylation
Resveratrol and analogues 771
modifiers 708
Retinoic acid (vitamin A) 772
Conclusions 710
Selenium (Se) 772
Glossary 712
Tannins 773
Abbreviations 712
Dietary phytochemicals and nutrients as
References 712
regulators of miRNAs 773
Apigenin 773
32. Modulation of noncoding RNAs Curcumin 786
(ncRNAs) and their potential role Epigallocatechin-3-gallate 787
as therapeutics Folate (vitamin B9) 787
Genistein 788
Luciano Pirola, Oskar Ciesielski,
Isothiocyanates 788
Marta Biesiekierska, and Aneta Balcerczyk
Indoles 789
Introduction 721 Lycopene 789
Noncoding RNA in the regulation of gene Organosulfur compounds 789
expression 721 Polyunsaturated fatty acids 790
Mechanism of gene regulation by miRNAs 722 Quercetin 790
RNA activation 723 Resveratrol and analogues 790
xiv  Contents

Retinoic acid (vitamin A) 791 Epigenetic modifications contribute to drug

Selenium (Se) 792 response and prognosis 844
Tannins 792 Response to clofarabine 845
Epigenetic clinical trials with dietary Response to cancer immunotherapy 845
phytochemicals and nutrients 795 Predicting prognosis and survival
Conclusions 795 in cancer 845
Acknowledgments 796 Novel cytosine modifications for precision
References 796 medicine 846
Diffuse large B-cell lymphoma 846
34. Epigenetics of pain management Multiple myeloma 846
Neuroblastoma 847
T. Louwies, A.C. Johnson, C.O. Ligon,
Challenges and perspectives 847
and B. Greenwood-Van Meerveld
Technical development 847
Introduction 817 Integrative and systems biology
Chronic pain states 817 approaches 848
Somatic pain 817 Conclusions 848
Visceral pain 819 References 849
Neuropathic pain 820
Role of epigenetic mechanisms 36. Epigenetics and regenerative medicine
in chronic pain 821
Devon Ehnes, Shiri Levy, and Hannele
DNA methylation 821
Ruohola-Baker
Histone tail modifications 822
Noncoding RNAs 824 Introduction 853
Future approaches to exploit the role of Epigenetic defects in aged tissues 853
epigenetics in chronic pain 825 Epigenetics and aging from a muscle
Role of sex differences in chronic pain 825 regeneration perspective: Satellite
Role of environmental stimuli stem cells 853
in chronic pain 826 New insights into epigenetics and aging
Role of immune-mediated disorders in other tissues can inform nascent fields:
in chronic pain 828 The salivary gland 856
Challenges and hurdles for epigenetic Epigenetic dysregulation in cognition and
therapies 831 neurodegeneration 859
Conclusion 831 Epigenetic dysregulation in developmental
References 831 plasticity and non-age-related brain
diseases 859
35. Precision medical epigenetics Age-related decline in cognition is linked
to the deregulation of epigenetic marks 859
Chang Zeng, Zhou Zhang, Xiaolong Cui,
Epigenetic remodeling tools used in
and Wei Zhang
regenerative medicine therapeutics 861
Enabling technologies for precision Epigenetic chemical inhibitors 861
epigenetic medicine 841 Epigenetic noncoding RNA used in
Conventional approaches 842 regenerative medicine 861
Single-cell approaches 842 Novel targeted epigenetic remodeler tools 862
Technologies for novel cytosine Applications of epigenetic remodelers in
modifications 843 regenerative medicine 863
Epigenetic modifications contribute to gene Epigenetic application tools in hESC
expression variations 843 and iPSC 863
Interindividual and interpopulation Future promise for epigenetic medical
epigenetic variation 844 therapy 866
Epigenetic variation partially explained Conclusion 866
by local genetic background 844 References 866
 Contents  xv

37. Stem cell epigenetics in medical Section H

therapy Medical epigenetics: Future prospects
Baoli Cheng, Liqi Shu, Emily G Allen,
and Peng Jin 39. Epigenetics: Future prospective in
human disorders and therapeutics
Introduction 873
Stem cells 873 Shriram N. Rajpathak, Vinayak S. Biradar, and
Epigenetics of stem cells 875 Deepti D. Deobagkar
DNA methylation 875
Introduction 903
Histone modifications 877
Epigenetics in stress and related disorders 903
Noncoding RNA 878
Early life events and stress biology 903
RNA modifications 878
Oxidative stress as a mediator for
Therapeutic prospects of stem cells 879
epigenetic changes 904
Summary 880
Stress and epigenetics machinery 904
Glossary 880
Stress-related disorders 905
Abbreviation 881
Epigenetics in human chromosomal disorders 907
References 881
Outline for an association between
aneuploidy and epigenetic machinery 907
38. The clinical landscape of HDAC Autosomal aneuploidy conditions 909
inhibitors Sex chromosomal aneuploidy 909
Non-coding RNAs as regulators in
A. Ganesan X monosomy and trisomy 913
Nucleosome modification and Future perspective 914
transcriptional regulation 885 References 914
One to eleven: The human zinc-dependent
HDACs 885 40. Prospective advances in medical
Nuclear protein deacetylases HDAC1, epigenetics
HDAC2, and HDAC3 885
Jiali Deng, Mengying Guo, and Junjie Xiao
Cytoplasmic protein deacetylase
HDAC6 886 Introduction 919
Protein fatty acid deacylases HDAC8 and Prospective advances of DNA methylation in
HDAC11 886 medical epigenetics 921
Polyamine deacetylase HDAC10 886 Prospective advances of DNA methylation
Pseudoenzymes HDAC4, HDAC5, HDAC7, in vitiligo 923
and HDAC9 886 Prospective advances of DNA methylation
HDAC inhibitors—A pharmacological in liver 923
classification 886 Prospective advances of DNA methylation age 926
Nonselective HDAC inhibitors 887 Prospective advances of DNA
Nuclear isoform selective HDAC methylation in neuron 926
inhibitors 889 Prospective advances of histone modification
HDAC6 and HDAC8 isoform selective in medical epigenetics 927
inhibitors 890 Prospective advances of noncoding RNAs
Dual mechanism HDAC inhibitors 891 in medical epigenetics 928
Advanced clinical trials—Hematological International Human Epigenome Consortium
cancers 892 and epigenetical precision medicine 930
Advanced clinical trials—Non-blood Limitations 931
cancers 893 Prospect 931
Advanced clinical trials—Beyond Acknowledgments 932
cancer 894 References 932
Summary 895
References 896 Index 937
This page intentionally left blank
Contributors
Numbers in parenthesis indicate the pages on which the authors’
­contributions begin.
Charbel Abi Khalil (197), Epigenetics Cardiovascular
Lab, Research Department, Weill Cornell Medicine-
Qatar, Doha, Qatar; Department of Genetic Medicine,
Weill Cornell Medicine, New York, United States; Joan
and Sanford I. Weill Department of Medicine, Weill
Cornell Medicine, New York, United States
Robert E. Akins (513), Center for Pediatric Clinical
Research and Development, Alfred I. duPont Hospital
for Children, Nemours Children’s Health System,
Wilmington, DE, United States
T. Alenghat (213), Division of Immunobiology and Center
for Immunology and Tolerance, Cincinnati Children’s
Hospital Medical Center; Department of Pediatrics,
University of Cincinnati College of Medicine,
Cincinnati, OH, United States
Emily G Allen (873), Department of Human Genetics,
Emory University, Atlanta, GA, United States
N. Altorok (251), Division of Rheumatology and
Immunology, Department of Internal Medicine,
University of Toledo Medical Center, Toledo, OH,
United States
Lucia Altucci (447), Department of Precision Medicine,
University of Campania “Luigi Vanvitelli”, Naples, Italy
Aneta Balcerczyk (721), Department of Molecular
Biophysics, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz, Poland
Isabel Barragán (117), Medical Oncology Service,
Section of Immuno-Oncology, Hospitales Universitarios
Regional y Virgen de la Victoria, Institute of Biomedical
Research in Malaga (IBIMA), Málaga, Spain; Group
of Pharmacoepigenetics, Department of Physiology
and Pharmacology, Karolinska Institutet, Stockholm,
Sweden
Marta Biesiekierska (721), Department of Molecular
Biophysics, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz, Poland
Vinayak S. Biradar (903), Molecular Biology Research
Laboratory, Department of Zoology, Savitribai Phule
Pune University, Pune, India
Sarah J. Blossom (171), Department of Pharmaceutical
Sciences, College of Pharmacy, University of New
Mexico Health Science Center, Albuquerque, NM,
United States
Patricia Chaves (171), Medical Oncology Service, Section
of Immuno-Oncology, Hospitales Universitarios
Regional y Virgen de la Victoria, Institute of Biomedical
Research in Malaga (IBIMA); University of Málaga,
Málaga, Spain
D. Chen (665), Department of Chemical and Pharmaceutical
Biology, University of Groningen, Groningen, The
Netherlands
Hong Chen (471), Department of Food Science and Human
Nutrition; Division of Nutritional Sciences, University
of Illinois at Urbana-Champaign, Urbana, IL, United
States
Shijia Alexia Chen (471), Department of Food Science
and Human Nutrition, University of Illinois at Urbana-
Champaign, Urbana, IL, United States
Baoli Cheng (873), Department of Human Genetics, Emory
University, Atlanta, GA, United States
P. Chun (597), College of Pharmacy, Inje University,
Gimhae, South Korea
Oskar Ciesielski (721), Department of Molecular
Biophysics, Faculty of Biology and Environmental
Protection; The Bio-Med-Chem Doctoral School of the
University of Lodz and Lodz Institutes of the Polish
Academy of Sciences, University of Lodz, Lodz, Poland
Maricarmen Colon-Diaz (309), San Juan Bautista Medical
School, Caguas, Puerto Rico
O.H. Cox (81), The Johns Hopkins Mood Disorders Center,
Department of Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine,
Baltimore, MD, United States
xvii
xviii  Contributors
Angela Cozma (143), University of Medicine and
Pharmacy; Department of 4th Internal Medicine, Cluj-
Napoca, Romania
Xiaolong Cui (839), Department of Chemistry, University
of Chicago, Chicago, IL, United States
F.J. Dekker (665), Department of Chemical and
Pharmaceutical Biology, University of Groningen,
Groningen, The Netherlands
Carmela Dell’Aversana (447), Institute for Experimental
Endocrinology and Oncology “Gaetano Salvatore”
(IEOS) – National Research Council (CNR); Department
of Precision Medicine, University of Campania “Luigi
Vanvitelli”, Naples, Italy
Engin Demirdizen (425), Neurology Clinic and National
Center for Tumor Diseases, University Hospital
Heidelberg, Heidelberg, Germany
Jiali Deng (919), Institute of Geriatrics (Shanghai
University), Affiliated Nantong Hospital of Shanghai
University (The Sixth People’s Hospital of Nantong),
School of Medicine, Shanghai University, Nantong;
Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Sciences, Shanghai Engineering
Research Center of Organ Repair, School of Life
Science, Shanghai University, Shanghai, China
Deepti D. Deobagkar (903), Molecular Biology Research
Laboratory, Department of Zoology, Savitribai Phule
Pune University, Pune, India
Mona Dvir-Ginzberg (633), Institute of Bio-Medical and
Oral Research, Faculty of Dental Medicine, Hebrew
University of Jerusalem, Jerusalem, Israel
Devon Ehnes (853), Institute for Stem Cell and
Regenerative Medicine; Department of Biochemistry,
School of Medicine, University of Washington, Seattle,
WA, United States
J.C. Eissenberg (103), Edward A. Doisy Department
of Biochemistry and Molecular Biology, Saint Louis
University School of Medicine, Doisy Research Center,
St Louis, MO, United States
Perla M. Elosegui (309), San Juan Bautista Medical
School, Caguas, Puerto Rico
Adriana Fodor (143), University of Medicine and
Pharmacy; Department of Diabetes, Nutrition and
Metabolic Diseases, Cluj-Napoca, Romania
A. Ganesan (885), School of Pharmacy, University of East
Anglia, Norwich, United Kingdom
Cristina Giorgio (447), Department of Precision Medicine,
University of Campania “Luigi Vanvitelli”, Naples, Italy
Mengying Guo (919), Institute of Geriatrics (Shanghai
University), Affiliated Nantong Hospital of Shanghai
University (The Sixth People’s Hospital of Nantong),
School of Medicine, Shanghai University, Nantong;
Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Sciences, Shanghai Engineering
Research Center of Organ Repair, School of Life
Science, Shanghai University, Shanghai, China
J.G. Hall (377), Department of Medical Genetics and
Pediatrics, University of British Columbia; BC
Children’s Hospital, Vancouver, BC, Canada
S. Hashimoto-Hill (213), Division of Immunobiology
and Center for Immunology and Tolerance, Cincinnati
Children’s Hospital Medical Center; Department of
Pediatrics, University of Cincinnati College of Medicine,
Cincinnati, OH, United States
Mustapha Umar Imam (33), Centre for Advanced
Medical Research and Training; Department of Medical
Biochemistry, Faculty of Basic Medical Sciences,
Usmanu Danfodiyo University, Sokoto, Nigeria
Maznah Ismail (33), Laboratory of Molecular Biomedicine,
Institute of Bioscience, Universiti Putra Malaysia, UPM,
Serdang, Selangor, Malaysia
Alexander J. Jaramillo (309), San Juan Bautista Medical
School, Caguas, Puerto Rico
M.P. Jennings (407), Institute for Glycomics, Griffith
University, Gold Coast, QLD, Australia
Peng Jin (873), Department of Human Genetics, Emory
University, Atlanta, GA, United States
A.C. Johnson (817), Oklahoma Center for Neuroscience,
University of Oklahoma Health Sciences Center; Veterans
Affairs Health Care System; Department of Physiology,
University of Oklahoma Health Sciences Center;
Department of Neurology, University of Oklahoma Health
Sciences Center, Oklahoma City, OK, United States
B. Kahaleh (251), Division of Rheumatology and
Immunology, Department of Internal Medicine, University
of Toledo Medical Center, Toledo, OH, United States
D.R. Kelly (213), Division of Immunobiology and Center
for Immunology and Tolerance, Cincinnati Children’s
Hospital Medical Center; Department of Pediatrics,
University of Cincinnati College of Medicine,
Cincinnati, OH, United States
Alexander Koliada (11), Molecular Genetic Laboratory
Diagen, Kyiv, Ukraine
Narasaiah Kolliputi (185), Division of Allergy and
Immunology, Department of Internal Medicine,
University of South Florida, Tampa, FL, Unites States

Ashok Kumar (633), Department of Biochemistry and
Biophysics, University of Rochester, Rochester, NY,
United States
R.S. Lee (81), The Johns Hopkins Mood Disorders Center,
Department of Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine,
Baltimore, MD, United States
Anait S. Levenson (741), Department of Veterinary
Biomedical Sciences, College of Veterinary Medicine,
Long Island University, Brookville, NY, United States
Shiri Levy (853), Institute for Stem Cell and Regenerative
Medicine; Department of Biochemistry, School of
Medicine, University of Washington, Seattle, WA,
United States
C.O. Ligon (817), Oklahoma Center for Neuroscience,
University of Oklahoma Health Sciences Center,
Oklahoma City, OK, United States
Maria Liguori (559), National Research Council, Institute
of Biomedical Technologies, Bari Unit, Bari, Italy
Ji Liu (347), Department of Ophthalmology and Visual
Science, Yale University School of Medicine, New
Haven, CT, United States
T. Louwies (817), Oklahoma Center for Neuroscience,
University of Oklahoma Health Sciences Center,
Oklahoma City, OK, United States
Qianjin Lu (231), Department of Dermatology, Second
Xiangya Hospital of Central South University, Hunan
Key Laboratory of Medical Epigenetics, Changsha,
Hunan, People’s Republic of China
Shuaihantian Luo (231), Department of Dermatology,
Second Xiangya Hospital of Central South University,
Hunan Key Laboratory of Medical Epigenetics,
Changsha, Hunan, People’s Republic of China
Oleh Lushchak (11), Department of Biochemistry and
Biotechnology, Vasyl Stefanyk Precarpathian National
University, Ivano-Frankivsk, Ukraine
B. Greenwood-Van Meerveld (817), Oklahoma Center
for Neuroscience, University of Oklahoma Health
Sciences Center; Veterans Affairs Health Care System;
Department of Physiology, University of Oklahoma
Health Sciences Center, Oklahoma City, OK, United
States
Rachel L. Miller (51), Icahn School of Medicine at Mount
Sinai Hospital, New York, NY, United States
V. Nagaraja (251), Division of Rheumatology, Department
of Internal Medicine University of Michigan, Ann
Arbor, MI, United States
Contributors  xix
Shyamala C. Navada (585), Tisch Cancer Institute, Icahn
School of Medicine at Mount Sinai, New York, NY,
United States
Nicoletta Nuzziello (559), National Research Council,
Institute of Biomedical Technologies, Bari Unit, Bari, Italy
Jessica Oh (51), Icahn School of Medicine at Mount Sinai
Hospital, New York, NY, United States
Elisa Oltra (279), Department of Pathology, School of
Health Sciences, Catholic University of Valencia,
Valencia, Spain
Juan Luis Onieva (117), Medical Oncology Service,
Section of Immuno-Oncology, Hospitales Universitarios
Regional y Virgen de la Victoria, Institute of Biomedical
Research in Malaga (IBIMA), Málaga, Spain
Der Jiun Ooi (33), Department of Oral Biology &
Biomedical Sciences, Faculty of Dentistry, MAHSA
University, Jenjarom, Selangor, Malaysia
Luciano Pirola (721), Cardiology, Metabolism and Nutrition
Laboratory, INSERM U1060, Lyon-1 University, South
Lyon Medical Faculty, Pierre Benite, France
S. Proschinger (491), Department for Molecular and
Cellular Sports Medicine, German Sport University
Cologne, Cologne, Germany
Shriram N. Rajpathak (903), Molecular Biology Research
Laboratory, Department of Zoology, Savitribai Phule
Pune University, Pune, India
Karyn G. Robinson (513), Tissue Engineering and
Regenerative Medicine Laboratory, Alfred I. duPont
Hospital for Children, Nemours Children’s Health
System, Wilmington, DE, United States
Gabriela Roman (143), University of Medicine and
Pharmacy; Department of Diabetes, Nutrition and
Metabolic Diseases, Cluj-Napoca, Romania
Hannele Ruohola-Baker (853), Institute for Stem Cell and
Regenerative Medicine; Department of Biochemistry,
School of Medicine, University of Washington, Seattle,
WA, United States
Adriana Rusu (143), University of Medicine and
Pharmacy; Department of Diabetes, Nutrition and
Metabolic Diseases, Cluj-Napoca, Romania
Kamaldeen Olalekan Sanusi (33), Department of
Physiology, Faculty of Basic Medical Sciences; Centre
for Advanced Medical Research and Training, Usmanu
Danfodiyo University, Sokoto, Nigeria
A. Schenk (491), Institute for Sport and Sport science, TU
Dortmund University, Dortmund, Germany
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Wealth, 136;
inheritance of, 229, 236;
as the basis of open classes, 248 ff.;
comparative ascendency of, 278 f.;
prestige of, 303 f.;
use of, 304 f.
We-feeling, 23, 31, 33 ff., 189 ff., 298, 333, 351, 415.
Westermarck, Edward, 24, 40 f.
Wharton, Edith, 102.
Whately, 150.
Whitman, 176, 195 f., 303.
Will, public, 395-419;
government as, 402 ff.;
some phases of, 411 ff.
See also Opinion, public.
Winckelmann, 78.
Women, opening of new careers to, 362 ff.
Woods, Robert, 43, 49.
Woolman, John, 413.
Wordsworth, 165, 317.
Worry, a cause of poverty, 297.
Writing, social function of, 72 ff.
Wrongs, social, not willed, 400 f.

Young Men, in relation to classes, 223, 273 f., 327.

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