Preface ....................................................... xxi
About the Editors ........................................... xxiii
List of Contributors .......................................... xxv
PART 1 GENERAL ASPECTS OF EPIGENETICS IN PSYCHIATRY
CHAPTER 1 Introduction to Epigenetics in Psychiatry ............ 3
Richard Lee and Dimitrios Avramopoulos
Introduction .................................................... 4
Genetics of psychiatric disorders ............................... 4
Schizophrenia ................................................ 6
Autism spectrum disorder ..................................... 8
Bipolar disorder ............................................. 9
Major depressive disorder .................................... 9
Attention deficit hyperactivity disorder .................... 10
Genotype versus phenotype ...................................... 10
Missing heritability ........................................... 10
Epigenetics in psychiatric disorders ........................... 12
Nutrition ................................................... 13
Prenatal infection .......................................... 14
Stress ...................................................... 14
Epigenetic versus genetic approaches to psychiatric disorders .. 16
Moving epigenetics forward ..................................... 18
Conclusion ..................................................... 19
References ..................................................... 20
Glossary ....................................................... 24
CHAPTER 2 Outline of Epigenetics ............................... 27
Bidisha Paul and Trygve O. Tollefsbol
Introduction ................................................... 28
Molecular mechanisms of epigenetics ............................ 29
DNA methylation ............................................. 29
DNA methylation, development, and disease ................... 31
Chromatin remodeling and histone modifications .............. 32
Histone acetylation ............................................ 32
Histone methylation ............................................ 34
Other histone modifications .................................... 34
Non-Coding RNA .............................................. 34
microRNA .................................................... 35
Correlation of epigenetics with genetics, transcriptomics,
and proteomics ................................................. 36
Clinical and medical implication of epigenetics ................ 37
Conclusion ..................................................... 38
Acknowledgments ................................................ 39
References ..................................................... 39
Glossary ....................................................... 43
CHAPTER 3 A Brief History of Epigenetics in Psychiatry ........ 45
Jacob Peedicayil
Introduction ................................................... 45
Erikson's epigenetic principle ................................. 46
Schizophrenia: the epigenetic puzzle ........................... 47
Later theoretical developments ................................. 47
Experimental (laboratory) studies on epigenetics in
psychiatry .................................................. 48
The social environment and epigenetics in psychiatry ........... 49
Conclusions .................................................... 49
References ..................................................... 49
Glossary ....................................................... 50
CHAPTER 4 Roles of Epigenetics in the Neural Stem Cell and
Neuron ......................................................... 51
Naoki Yamamoto, Masahiro Uesaka, Takuya Imamura, and Kinichi
Nakashima
Outline of neural cell production during cortical
development .................................................... 53
Epigenetic regulation of exit from cell proliferation cycle
toward postmitotic neurons during early cortical development ... 54
Epigenetic regulation underlying properties of multipotent
neural stem cells and their differentiation into upper layer
cortical neurons and astrocytes ................................ 55
Epigenetic regulation of postnatal oligodendrocyte
differentiation and adult neurogenesis ......................... 58
Combination of taws-acting epigenetic modifiers involved in
epigenome formation ............................................ 59
Importance of focusing on epigenetics in neuronal functions .... 62
Impact of epigenetic regulation on synaptic plasticity,
learning, and memory ........................................... 63
Plasticity of epigenetic profile in neurons in response to
extrinsic stimuli .............................................. 65
The robust identity of neurons defined by the epigenetic
status ......................................................... 69
Concluding remarks ............................................. 72
Acknowledgments ................................................ 73
References ..................................................... 73
Glossary ....................................................... 77
CHAPTER 5 Role of Epigenetics in the Brain .................... 79
Stephanie Matt, Eric D. Roth, and Tania L. Roth
Introduction ................................................... 80
Role of epigenetics in evolution ............................... 81
Role of epigenetics in brain development ....................... 83
Brain development ........................................... 83
Epigenetics in early brain development ...................... 85
Epigenetics in adult neurogenesis and later brain
maturation .................................................. 88
Epigenetics and extrinsic factors regulating brain
development ................................................. 89
Role of epigenetic mechanisms in brain function ................ 90
Epigenetics and memory ...................................... 90
Epigenetics and stress ...................................... 91
Epigenetics and cognitive dysfunction ....................... 93
Concluding remarks ............................................. 94
Acknowledgments ................................................ 95
References ..................................................... 95
Glossary ....................................................... 99
CHAPTER 6 Epigenetic Epidemiology of Psychiatric Disorders ... 101
Monica Uddin, Angela Bustamante, and Satoshi Toyokawa
Introduction .................................................. 103
Causal inference in epigenetic epidemiology ................... 103
Study designs in epigenetic epidemiology ...................... 105
Methodologie issues to consider in epigenetic epidemiology .... 114
Tissue and cell specificity of epigenetic marks ............ 114
Defining mechanistic relationships among DNA sequence,
epigenetic, and gene expression variation .................. 116
Unknown effect sizes in disease-associated epigenetic
variation .................................................. 118
Importance of a life course perspective ....................... 118
Conclusions ................................................... 122
References .................................................... 122
Glossary ...................................................... 127
CHAPTER 7 Laboratory Techniques in Psychiatric Epigenetics ... 111
Chris Murgatroyd
Introduction .................................................. 131
DNA methylation ............................................... 131
Global quantification of DNA methylation ...................... 132
Higher resolution analyses of DNA methylation ................. 133
Sodium bisulfite treatment ................................. 133
Restriction enzyme digestion ............................... 134
Affinity capture ........................................... 136
Gene-specific quantification of DNA methylation ............... 137
Methylation-specific PCR methods ........................... 137
Bisulfite sequencing approaches ............................ 138
Methylated DNA affinity enrichment approaches .............. 141
Genome-wide DNA methylation analysis .......................... 142
Microarray-based methylation approaches .................... 142
Next-generation sequencing-based methylation analysis ...... 143
Roche/454 sequencing of converted-converted DNA ............ 144
SOLiD™ sequencing of converted-converted DNA ............... 144
Illumina sequencing of converted-converted DNA ............. 145
Ion torrent ................................................ 145
Genome approaches ............................................. 145
5hmC approaches ............................................... 146
Chromatin ..................................................... 148
Global histone analyses ....................................... 149
Sequence-specific and genome-wide histone analyses ............ 149
Chromatin immunoprecipitation (ChIP) ....................... 149
Analyzing multiple binding events .......................... 152
Gene-specific ChIP ......................................... 152
Genome-wide ChIP ........................................... 152
Open chromatin ............................................. 153
Mapping chromatin interactions ............................. 154
Conclusion .................................................... 156
References .................................................... 156
Glossary ...................................................... 161
CHAPTER 8 Laboratory Epigenetic Models of Schizophrenia
Jacob Peedicayil, Erbo Dong, and Dennis R. Grayson
Introduction .................................................. 164
Laboratory non-epigenetic models of schizophrenia ............. 164
In vitro non-epigenetic models of schizophrenia ............ 165
In vivo rodent non-epigenetic models of schizophrenia ...... 165
Mimicking schizophrenia: chronic d-lysergic acid
diethylamide administration to simulate psychosis ............. 165
In vivo epigenetic models of schizophrenia .................... 166
L-methionine-induced hypermethylation (MIH) model of
schizophrenia .............................................. 166
Assessment of L-methionine-induced hypermethylation model of
schizophrenia ................................................. 167
Prenatal restraint stress model for schizophrenia ............. 168
Prenatal restraint stress model in mice ....................... 168
Prenatal restraint stress model in rats ....................... 169
Assessment of prenatal restraint stress as an epigenetic
model of schizophrenia ........................................ 170
Prenatal infection models ..................................... 171
In vitro epigenetic cell-based models of schizophrenia ........ 171
Epigenetic models of schizophrenia based on cell culture ... 171
NT2 neuronal precursor cells ............................... 172
Primary neuronal cultures .................................. 172
Induced human pluripotent stem cells ....................... 174
Assessment of epigenetic cell-based models of
schizophrenia .............................................. 175
Conclusions ................................................... 175
References .................................................... 176
Glossary ...................................................... 179
CHAPTER 9 Animal Models of Environmental Manipulations
Resulting in Epigenetic Modifications That Increase Risk for
Affective Disorders ........................................... 181
Sarah Adams Schoenrock and Lisa M. Tarantino
Mood disorders ................................................ 182
Rationale for the use of animal models ........................ 183
Mood and anxiety-like phenotypes in rodents ................... 184
Prenatal exposures ............................................ 184
Maternal mood and stress ................................... 185
Exposure to toxins ......................................... 186
Nutritional deficiencies ................................... 187
Postnatal exposures ........................................... 188
Maternal care and bonding .................................. 188
Maternal abuse and neglect ................................. 190
Adulthood exposures ........................................... 191
Social stress .............................................. 192
Stressful life events ...................................... 192
Reproductive hormones ...................................... 193
Future directions ............................................. 194
Sex differences in epigenetic modifications ................ 194
New experimental populations ............................... 194
Measure gene-specific modifications ........................ 195
Conclusions ................................................... 196
References .................................................... 197
Glossary ...................................................... 205
PART 2 EPIGENETICS OF PSYCHIATRIC DISORDERS
CHAPTER 10 5-Methycytosine and 5-Hydroxymethylcytosine in
Psychiatric Epigenetics ....................................... 209
Dennis R. Grayson and Alessandro Guidotti
Introduction to the epigenome ................................. 210
CpG islands and DNA methylation ............................... 213
DNA methylating enzymes ....................................... 214
DNMT1 overexpression in psychosis ............................. 217
DNA methylation biomarkers .................................... 217
Genome-wide methylation studies ............................... 219
Genome-wide array-based methods ............................... 219
Methylation of BDNF in psychiatric disorders .................. 221
Array-based studies for SZ .................................... 224
Second-generation methylation arrays and SZ ................... 226
Enrichment sequencing for studies of SZ ....................... 226
Genome-wide studies of methylation in ASD ..................... 227
Hydroxymethylcytosine historical perspective .................. 229
5-hmC in psychiatric disorders ................................ 231
Summary and conclusions ....................................... 231
References .................................................... 232
Glossary ...................................................... 239
CHAPTER 11 Pathogenic Histone Modifications in Schizophrenia
are Targets for Therapy ....................................... 241
Hamid Mostafavi Abdolmaleky and Sam Thiagalingam
A brief introduction to histone modifications ................. 242
Histone methylation and schizophrenia pathogenesis ............ 243
Aberrant histone acetylation in schizophrenia ................. 244
Other types of histone modifications associated with SZ
pathogenesis .................................................. 245
Current therapeutic targets modulating histone codes .......... 246
Methodological challenges of histone modification analyses .... 247
Conclusion and perspectives ................................... 248
References .................................................... 248
Glossary ...................................................... 251
CHAPTER 12 Non-Coding RNAs and Psychiatric Disorders .......... 253
Jacob Peedicayil and Natalie J. Beveridge
Introduction .................................................. 254
Types and functions of non-coding RNAs ........................ 254
Role of non-coding RNAs in the brain .......................... 256
Role of non-coding RNAs in schizophrenia ...................... 257
Studies on postmortem brain ................................ 258
Studies on peripheral tissues .............................. 259
Role of non-coding RNAs in bipolar disorder ................... 260
Studies on postmortem brain ................................ 260
Studies on peripheral tissues .............................. 260
Role of non-coding RNAs in major depressive disorder ....... 260
Studies on postmortem brain ................................ 260
Studies on peripheral tissues .............................. 261
Polymorphisms of genes encoding miRNAs associated with
psychiatric disorders ......................................... 261
Conclusions and future directions ............................. 261
References .................................................... 262
Glossary ...................................................... 264
CHAPTER 13 Epigenetics of Bipolar Disorder .................... 265
Gen Shinozaki, Benjamin Hing, and James B. Potash
The epigenetic hypothesis in bipolar disorder ................. 266
Epigenetic mechanisms ......................................... 267
Direct examination of epigenetic impact from the study of
bipolar disorder .............................................. 268
Single-gene DNA methylation studies and bipolar disorder ...... 270
Genome-wide methylation studies and bipolar disorder .......... 271
Histone modifications studies and bipolar disorder ............ 272
Epigenetics of stress as an entry point ....................... 273
Epigenetics of neuroplasticity ................................ 274
Future directions ............................................. 274
Conclusions ................................................... 275
References .................................................... 276
Glossary ...................................................... 278
CHAPTER 14 Epigenetics in Major Depressive Disorder ........... 279
Zachary A. Kaminsky
Introduction .................................................. 280
What is major depression? ..................................... 281
Brain imaging endophenotypes in MDD ........................... 281
Two genetically driven hypotheses of depression ............... 282
Nature and nurture in MDD ..................................... 283
GWAS and the missing heritability ............................. 284
Environmental influence, epigenetics, and the missing
heritability .................................................. 284
Maternal diet and epigenetically mediated effects on
neurodevelopment outcomes ..................................... 285
Gestational consequences of maternal stress ................... 286
Early-life adversity-mediated epigenetic reprogramming ........ 287
The epigenetic intersect of gonadal hormonal fluctuation and
mood .......................................................... 288
Inflammation .................................................. 290
The effects of glucocorticoid system disruption in MDD ........ 290
Epigenetic etiology and brain imaging endophenotype ........... 292
DNA methylome scans in MDD .................................... 293
Conclusion .................................................... 294
References .................................................... 295
Glossary ...................................................... 302
CHAPTER 15 The Epigenetics of Suicide: The Critical Impact
of the Environment on Epigenetic Regulation in Suicide ....... 303
Benoit Labonté, Pierre-Eric Lutz, and Gustavo Turecki
Suicide perspectives .......................................... 304
The molecular consequences of early-life adversity:
Transcriptional regulation by epigenetic mechanisms ........... 306
Glucocorticoid receptor .................................... 306
Corticotropin-releasing hormone ............................ 308
Arginine vasopressin ....................................... 309
Neurotrophic factors ....................................... 309
Other epigenetic alterations in suicide brains ................ 311
Ribosomal RNA gene ......................................... 311
Polyamine system ........................................... 311
GABAergic system ........................................... 311
Serotonergic system ........................................ 312
Investigating genome-wide DNA methylation patterns ............ 313
Toward an integrative model of stress-induced
psychopathology ............................................... 314
Concluding remarks ............................................ 316
References .................................................... 316
Glossary ...................................................... 324
CHAPTER 16 Epigenetics in Posttraumatic Stress Disorder ....... 325
Richard G. Hunter
Introduction .................................................. 326
The lasting impact of early adversity ......................... 327
HPA axis in PTSD and stress-related disorders ................. 328
Epigenetic effects of stress .................................. 330
Stress and trauma in development ........................... 330
Stress and trauma in adult life ............................ 332
Implications of epigenetics for the treatment of PTSD and
related disorders ............................................. 334
Conclusions ................................................... 335
Acknowledgments ............................................... 335
References .................................................... 336
Glossary ...................................................... 341
CHAPTER 17 Epigenetics and Cognitive Disorders ................ 343
Fabio Coppedè
Introduction: role of epigenetics in memory and
neurodegeneration ............................................. 345
DNA methylation ............................................ 345
Histone modifications ...................................... 347
DNA methylation changes and histone modifications in
Alzheimer's disease ........................................... 348
DNA methylation changes in Alzheimer's disease: cell
cultures and animal models ................................. 349
DNA methylation changes in Alzheimer's disease:
postmortem brains .......................................... 352
DNA methylation changes in Alzheimer's disease:
peripheral blood cells ..................................... 353
Histone modifications in Alzheimer's disease ............... 354
DNA methylation changes and histone modifications in
Huntington's disease .......................................... 355
DNA methylation changes in Huntington's disease ............ 356
Histone modifications in Huntington's disease .............. 357
DNA methylation changes and histone modifications in
Parkinson's disease ........................................... 358
DNA methylation changes in Parkinson's disease: cell
cultures and animal models ................................. 359
DNA methylation changes in Parkinson's disease:
individuals ................................................ 359
Histone modifications in Parkinson's disease ............... 360
Conclusions ................................................... 362
References .................................................... 362
Glossary ...................................................... 367
CHAPTER 18 Epigenetics in intellectual Disability ............. 369
Nathalie G. Bérubé and Jamie M. Kramer
Introduction .................................................. 371
Definition of epigenetics .................................. 372
Types of epigenetic disruption in ID ....................... 372
Abnormal epigenetic silencing in ID ........................... 372
Fragile X syndrome is caused by trinucleotide repeat
expansion and abnormal epigenetic silencing of FMR1 ........ 372
Genomic imprinting of the chromosome 15q11q13 region in
Prader-Willi and Angelman syndromes ........................... 373
Mutations in genes encoding epigenetic regulators ............. 376
DNA methylation in ID ......................................... 376
Disruption of DNA methyltransferases in ID ................. 376
Methyl-CpG-binding protein, MeCP2, and Rett syndrome ....... 377
Disruption of ATP-dependent chromatin remodeling in ID ........ 379
Alpha thalassemia mental retardation syndrome and the
ATRX protein ............................................... 379
Mutations in core members of the BAF chromatin remodeling
complex cause ID ........................................... 380
Mutations in the CHD chromatin remodeling family cause
ID, autism, and epilepsy ................................... 381
SRCAP mutations cause Floating-Harbor syndrome ............. 382
Histone methylation in ID ..................................... 382
Disruption of COMPASS-like complexes causes III ............ 382
Kleefstra syndrome is caused by mutations in EHMT1 ......... 384
Disruption of the histone methyltransferases NSD1 and
EZH2 causes ID-associated overgrowth disorders ............. 384
Disruption of histone demethylases causes ID ............... 385
Histone acetylation in ID ..................................... 385
Histone acetyltransferases in ID ........................... 385
Histone deacetylases in ID ................................. 386
Histone ubiquitination in ID .................................. 386
Summary and conclusions ....................................... 387
References .................................................... 387
Glossary ...................................................... 393
CHAPTER 19 Epigenetics and Pervasive Developmental Disorders .. 395
Andrea L. Gropman
Introduction .................................................. 397
Autism spectrum disorders and neurodevelopmental
disabilities ............................................... 397
Common pathways and mechanisms in NDDs ..................... 399
Epigenetics as an explanation of variability in
developmental disorders .................................... 399
Control of transcription is key in the process of gene
expression and is the first line of epigenetic control ..... 400
Epigenetic mechanisms and intellectual and neurodevelopmental
disabilities .................................................. 400
How do epigenetic modifications contribute to diversity? ...... 402
Examples of human neurodevelopmental disorders with
autistic features linking epigenetics and phenotype
variation .................................................. 403
Epigenetics and imprinting disorders ....................... 406
Epigenetic interactions between ASD and NDD conditions ..... 408
X-linked disorders associated with ID ...................... 408
Copy number variations ..................................... 410
Can drugs be developed for NDDs based on epigenetics? ......... 415
Conclusions ................................................... 417
References .................................................... 417
Glossary ...................................................... 423
CHAPTER 20 Epigenetics in Child Psychiatry .................... 425
Josephine Elia, Richard Kingsley, Oliver Yost, Charles
Bongiorno, Carolyn Bernacki, Alexander Ambmsini, Makiko
Okuyama, and Hakon Hakonarson
Introduction .................................................. 426
Epigenetic mechanisms ......................................... 427
DNA methylation ............................................ 427
Chromosome organization .................................... 427
Transcription factors ...................................... 427
Posttranslational regulation ............................... 429
Epigenetic processes and child psychiatric disorders .......... 429
Attention deficit hyperactivity disorder ................... 429
Autism ..................................................... 430
Psychotropic drugs and gene expression ........................ 431
Psychotropic drugs and epigenetics ............................ 431
Histone modifications ...................................... 431
DNA methylation ............................................ 434
miRNAs ..................................................... 434
Adverse effects of psychotropic drugs ......................... 434
Immediate early genes ...................................... 435
Conclusion .................................................... 436
References .................................................... 436
Glossary ...................................................... 440
CHAPTER 21 Epigenetic Mechanisms of Drug Addiction
Vulnerability ................................................. 441
Wendy Wenderski and Ian Maze
Introduction .................................................. 443
Epigenetic regulation of gene expression ...................... 443
Epigenetic mechanisms in addiction ............................ 444
Acute drug exposure: rapid and specific epigenetic responses .. 445
Histone acetylation ........................................ 445
Histone phosphorylation .................................... 446
Histone methylation ........................................ 447
Chromatin remodeling ....................................... 447
DNA methylation ............................................ 447
Non-coding RNAs ............................................ 448
Chronic drug use .............................................. 448
Histone acetylation ........................................ 448
Histone methylation ........................................ 449
Chromatin remodeling ....................................... 450
DNA methylation ............................................ 450
Non-coding RNAs ............................................ 451
Vulnerability to drug addiction ............................... 452
Early-life stress ............................................. 452
Mood disorders ................................................ 453
Environmental enrichment ...................................... 455
Prior drug exposure ........................................... 455
Gestational drug exposure ..................................... 456
Epigenetic inheritance of addiction ........................... 456
Future directions ............................................. 457
Conclusions ................................................... 457
References .................................................... 458
Glossary ...................................................... 461
CHAPTER 22 Mitoepigenetics and Neuropsychiatrie Disorders ..... 463
Hari Manev
Mitoepigenetics overview and relevance for brain disorders .... 464
Mitochondrial epigenetics ..................................... 466
mtDNA methylation .......................................... 467
mtDNA hydroxymethylation ................................... 469
mitosRNAs .................................................. 470
Mitochondria and nDNA epigenetics ............................. 470
Epigenetics of nDNA-encoded mitochondrial genes ............... 471
Future directions ............................................. 472
Methodological issues ...................................... 472
Mechanistic issues ......................................... 473
Mitoepigenetic biomarkers .................................. 473
Conclusion .................................................... 473
References .................................................... 474
Glossary ...................................................... 477
PART 3 EPIGENETIC THERAPY OF PSYCHIATRIC DISORDERS
CHAPTER 23 Epigenetic Effects of Currently Used
Psychotropic Drugs ............................................ 481
Marco P.M. Boks
Epigenetic effects of valproic acid ........................... 482
Valproic acid and chromatin marks .......................... 483
Valproic acid and DNA methylation .......................... 484
Epigenetic effects of antidepressants ......................... 484
Imipramine ................................................. 485
Amitriptyline .............................................. 486
Clomipramine ............................................... 486
Duloxetine ................................................. 486
Fluoxetine ................................................. 486
Escitalopram ............................................... 487
Monoamine Oxidase Inhibitors ............................... 487
Epigenetic effects of antipsychotics .......................... 487
Haloperidol ................................................ 488
Pimozide ................................................... 488
Clozapine .................................................. 488
Olanzapine ................................................. 489
Sulpiride and amisulpiride ................................. 489
Risperidone ................................................ 489
Antipsychotics and microRNAs ............................... 489
Epigenetic effects of Lithium salts ........................... 489
Conclusion .................................................... 490
References .................................................... 492
Glossary ...................................................... 496
CHAPTER 24 DNA Methyltransferase Inhibitors and Psychiatric
Disorders ..................................................... 497
Marija Kundakovic
Introduction .................................................. 498
DNA methylation and DNMTs ..................................... 499
DNA methylation and DNMTs in the developing and adult brain ... 501
DNMT inhibitors: currently available drugs and their
mechanisms of action .......................................... 502
Experimental use of DNMT inhibitors in neuroscience research:
relevance for learning and memory ............................. 504
Therapeutic potential of DNMT inhibitors in schizophrenia ..... 504
Therapeutic potential of DNMT inhibitors in depression ........ 506
Therapeutic potential of DNMT inhibitors in bipolar
disorders ..................................................... 508
Therapeutic potential of DNMT inhibitors in posttraumatic
stress disorder ............................................... 508
Conclusions, future directions, and challenges ................ 509
References .................................................... 509
Glossary ...................................................... 514
CHAPTER 25 Histone Deacetylase Inhibitors and Psychiatric
Disorders ..................................................... 515
Sumana Chakravarty, Unis Ahmad Bhat, R. Gajendra Reddy,
Praveer Gupta, and Arvind Kumar
Introduction .................................................. 516
HATs and HDACs maintain transcription homeostasis ............. 517
HDACs ......................................................... 518
HDAC types .................................................... 518
HDACs in normal brain, behavior and in psychopathology ........ 518
HDAC class 1 ............................................... 518
HDAC class IIa ............................................. 520
HDAC class IIb ............................................. 521
HDAC class III ............................................. 521
HDAC class IV .............................................. 521
HDAC inhibitors ............................................... 522
Clinical trials of HDACi ...................................... 523
HDACi tested in animal models of neuropsychiatrie disorders ... 523
HDACi in psychotic disorders (e.g., schizophrenia, bipolar
disorder) ..................................................... 523
HDACi in MDD .................................................. 529
HDACi in drug addiction ....................................... 530
HDACi in neurological disorders ............................... 530
HDACi classes ................................................. 531
Short-chain fatty acids (COOH group) ....................... 531
Hydroxamates (NHOH group) .................................. 531
Benzamides (PhNH2) ......................................... 533
Cyclic tetrapeptides ....................................... 533
Ketone group ............................................... 534
Constraints in the development of HDACi as therapeutics for
CNS disorders ................................................. 535
Recent efforts to develop selective HDACi ..................... 535
Design of future HDACi for psychiatric disorders .............. 535
Acknowledgments ............................................... 538
References .................................................... 538
Glossary ...................................................... 544
PART 4 OTHER TOPICS IN EPIGENETICS IN PSYCHIATRY
CHAPTER 26 The Social Environment and Epigenetics in
Psychiatry .................................................... 547
Patrick O. McGowan, Aya Sasaki, and Tania L. Roth
Introduction: social factors, genes, and gene expression
programming ................................................... 548
How mechanisms of gene regulation "above the genome"
contribute to interindividual differences in behavior ......... 549
Overview of epigenetic mechanisms ............................. 549
Targeting of epigenetic modifications to specific genes ....... 550
Epigenetic mechanisms and mental health ....................... 550
The response of epigenetic machinery to environmental signals . 551
Social factors associated with epigenetic modifications
during sensitive periods of development ....................... 552
Maternal care, epigenetics, and the HPA axis: laboratory
animal studies ................................................ 553
Parental care, epigenetics, and the HPA axis: human studies ... 554
Social factors associated with epigenetic modifications
outside of sensitive periods of development ................... 555
Social stress, epigenetics, and the HPA axis: laboratory
animal studies ............................................. 555
Social stress, epigenetics, and the HPA axis: human
studies .................................................... 557
Conclusion .................................................... 557
Acknowledgment ................................................ 558
References .................................................... 558
Glossary ...................................................... 562
CHAPTER 27 Nutritional Effects on Epigenetics in Psychiatry ... 563
Jacob Peedicayil
Introduction .................................................. 564
Nutritional epigenetics: the link between nutrition and
epigenetics ................................................... 564
Effect of nutrition on DNA methylation ........................ 564
Effect of nutrition on histone modifications .................. 566
Effect of nutrition on RNA-mediated regulation of gene
expression .................................................... 566
Nutritional effects on epigenetics in psychiatry .............. 567
Effect of prenatal nutrition on epigenetics in psychiatry ..... 567
Effect of postnatal nutrition on epigenetics in psychiatry .... 568
Transgenerational (heritable) effects of nutrition on
epigenetics in psychiatry ..................................... 569
Clinical applications of nutritional effects on epigenetics
in psychiatry ................................................. 569
Use of methyl donors in major depressive disorder ............. 570
Use of methyl donors in major psychosis ....................... 571
Use of methyl donors in cognitive disorders ................... 571
Conclusions ................................................... 571
References .................................................... 572
Glossary ...................................................... 575
CHAPTER 28 Transgenerational (Heritable) Epigenetics and
Psychiatric Disorders ......................................... 577
Tamara Brook Franklin
A novel non-Mendelian mechanism of inheritance ................ 578
Non-Mendelian patterns of expression of endogenous genes ... 578
Agouti viable yellow (Aνy) and axin-fused (AxinFu) ......... 578
Exposure to environmental toxicants ........................ 579
Metabolic influences ....................................... 581
Molecular mechanisms for epigenetic inheritance ............... 581
DNA methylation ............................................ 582
Posttranslational modifications on chromatin ............... 583
RNAs (RNA, miRNA, piRNA) ................................... 584
Paternal genome ............................................ 585
Epigenetic inheritance of psychiatric disorder-related
behavior in animal models ..................................... 585
Stress-induced behavior .................................... 585
Adult drug use ............................................. 588
Conclusion .................................................... 588
References .................................................... 589
Glossary ...................................................... 591
Abbreviations ................................................. 593
Glossary ...................................................... 609
Index ......................................................... 621
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