Transgenerational Epigenetic Effects on Brain Functions

Psychiatric diseases are multifaceted disorders with complex etiology, recognized to have strong heritable components. Despite intense research efforts, genetic loci that substantially account for disease heritability have not yet been identified. Over the last several years, epigenetic processes have emerged as important factors for many brain diseases, and the discovery of epigenetic processes in germ cells has raised the possibility that they may contribute to disease heritability and disease risk. This review examines epigenetic mechanisms in complex diseases and summarizes the most illustrative examples of transgenerational epigenetic inheritance in mammals and their relevance for brain function. Environmental factors that can affect molecular processes and behavior in exposed individuals and their offspring, and their potential epigenetic underpinnings, are described. Possible routes and mechanisms of transgenerational transmission are proposed, and the major questions and challenges raised by this emerging field of research are considered.

[1]  Thurston H. Y. Dang,et al.  The penetrance of an epigenetic trait in mice is progressively yet reversibly increased by selection and environment , 2012, Proceedings of the Royal Society B: Biological Sciences.

[2]  M. Bartolomei,et al.  Imprinting and epigenetic changes in the early embryo , 2009, Mammalian Genome.

[3]  Eva Jablonka,et al.  Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution , 2009, The Quarterly Review of Biology.

[4]  Michael Weber,et al.  Targets and dynamics of promoter DNA methylation during early mouse development , 2010, Nature Genetics.

[5]  P. Zamore,et al.  Small silencing RNAs: an expanding universe , 2009, Nature Reviews Genetics.

[6]  David I. K. Martin,et al.  A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice , 2011, PLoS genetics.

[7]  A. Ferguson-Smith,et al.  Mammalian genomic imprinting. , 2011, Cold Spring Harbor perspectives in biology.

[8]  C. Rosenfeld Animal Models to Study Environmental Epigenetics1 , 2010, Biology of reproduction.

[9]  A. Paoloni-Giacobino,et al.  Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm. , 2010, Reproduction.

[10]  L. Harper,et al.  Epigenetic inheritance and the intergenerational transfer of experience. , 2005, Psychological bulletin.

[11]  M. Skinner,et al.  Environmentally induced epigenetic transgenerational inheritance of phenotype and disease , 2012, Molecular and Cellular Endocrinology.

[12]  M. Dragunow,et al.  Pharmacology of epigenetics in brain disorders , 2010, British journal of pharmacology.

[13]  I. Weaver Epigenetic Programming by Maternal Behavior and Pharmacological Intervention Nature Versus Nurture: Let's Call The Whole Thing Off , 2007, Epigenetics.

[14]  K. Morris,et al.  Small Interfering RNA-Induced Transcriptional Gene Silencing in Human Cells , 2004, Science.

[15]  K. Wagner,et al.  RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse. , 2008, Developmental cell.

[16]  W. Reik,et al.  Epigenetic Reprogramming in Plant and Animal Development , 2010, Science.

[17]  Ravi Sachidanandam,et al.  A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. , 2008, Molecular cell.

[18]  E. Nestler,et al.  Paternal Transmission of Stress-Induced Pathologies , 2011, Biological Psychiatry.

[19]  T. Bale,et al.  Early Prenatal Stress Epigenetically Programs Dysmasculinization in Second-Generation Offspring via the Paternal Lineage , 2011, The Journal of Neuroscience.

[20]  C. Nemeroff,et al.  The link between childhood trauma and depression: Insights from HPA axis studies in humans , 2008, Psychoneuroendocrinology.

[21]  P. Sætrom,et al.  MicroRNA-directed transcriptional gene silencing in mammalian cells , 2008, Proceedings of the National Academy of Sciences.

[22]  S. Drăghici,et al.  A survey of small RNAs in human sperm. , 2011, Human reproduction.

[23]  Ky Sha,et al.  A mechanistic view of genomic imprinting. , 2008, Annual review of genomics and human genetics.

[24]  S. Krawetz,et al.  Cleavage of rRNA ensures translational cessation in sperm at fertilization. , 2011, Molecular human reproduction.

[25]  P. Sham,et al.  Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases , 2011, Genetic epidemiology.

[26]  Michael K. Skinner,et al.  Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility , 2005, Science.

[27]  J. Tost,et al.  DNA methylation: an introduction to the biology and the disease-associated changes of a promising biomarker. , 2009, Methods in molecular biology.

[28]  F. Holsboer,et al.  Dynamic DNA methylation programs persistent adverse effects of early-life stress , 2009, Nature Neuroscience.

[29]  R. Feil,et al.  Differential histone modifications mark mouse imprinting control regions during spermatogenesis , 2007, The EMBO journal.

[30]  P. Gluckman,et al.  Towards a new developmental synthesis: adaptive developmental plasticity and human disease , 2009, The Lancet.

[31]  J. Kelly,et al.  The impact of environmental enrichment in laboratory rats—Behavioural and neurochemical aspects , 2011, Behavioural Brain Research.

[32]  Chunyu Liu,et al.  After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. , 2011, The American journal of psychiatry.

[33]  David I. K. Martin,et al.  Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation , 2006, Proceedings of the National Academy of Sciences.

[34]  I. Mansuy,et al.  Inheritable Effect of Unpredictable Maternal Separation on Behavioral Responses in Mice , 2011, Front. Behav. Neurosci..

[35]  Holger Russig,et al.  Epigenetic Transmission of the Impact of Early Stress Across Generations , 2010, Biological Psychiatry.

[36]  C. Hales,et al.  Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis , 1992, Diabetologia.

[37]  C. Bountra,et al.  Epigenetic protein families: a new frontier for drug discovery , 2012, Nature Reviews Drug Discovery.

[38]  E. Nestler,et al.  Transcriptional and epigenetic mechanisms of addiction , 2011, Nature Reviews Neuroscience.

[39]  A. Hannan,et al.  Enriched environments, experience-dependent plasticity and disorders of the nervous system , 2006, Nature Reviews Neuroscience.

[40]  H. Taylor,et al.  Hypermethylation of homeobox A10 by in utero diethylstilbestrol exposure: an epigenetic mechanism for altered developmental programming. , 2009, Endocrinology.

[41]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[42]  M. Esteller,et al.  Cancer epigenetics reaches mainstream oncology , 2011, Nature Medicine.

[43]  S. Haggarty,et al.  An epigenetic blockade of cognitive functions in the neurodegenerating brain , 2012, Nature.

[44]  P. Muglia,et al.  Genome-wide association study of major recurrent depression in the U.K. population. , 2010, The American journal of psychiatry.

[45]  Y. Liu,et al.  Maternal Deprivation in Rats is Associated with Corticotrophin‐Releasing Hormone (CRH) Promoter Hypomethylation and Enhances CRH Transcriptional Responses to Stress in Adulthood , 2012, Journal of neuroendocrinology.

[46]  J. Sweatt,et al.  Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene , 2009, Biological Psychiatry.

[47]  S. Scarpino,et al.  Epigenetic transgenerational inheritance of altered stress responses , 2012, Proceedings of the National Academy of Sciences.

[48]  T. Hamatani Human spermatozoal RNAs. , 2012, Fertility and sterility.

[49]  F. Champagne Epigenetic mechanisms and the transgenerational effects of maternal care , 2008, Frontiers in Neuroendocrinology.

[50]  Isabelle M. Mansuy,et al.  Epigenetic inheritance in mammals: Evidence for the impact of adverse environmental effects , 2010, Neurobiology of Disease.

[51]  Patrick O. McGowan,et al.  Broad Epigenetic Signature of Maternal Care in the Brain of Adult Rats , 2011, PloS one.

[52]  R. Jirtle,et al.  Environmental epigenomics and disease susceptibility , 2007, Nature Reviews Genetics.

[53]  Scott T. Younger,et al.  Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters , 2011, Nucleic acids research.

[54]  R. Mishra,et al.  The paternal hidden agenda: Epigenetic inheritance through sperm chromatin , 2010, Epigenetics.

[55]  K. Lao,et al.  Sperm-borne microRNA-34c is required for the first cleavage division in mouse , 2011, Proceedings of the National Academy of Sciences.

[56]  M. Travisano,et al.  Diet‐induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[57]  I. Mansuy,et al.  Epigenetic modifications of the neuroproteome , 2012, Proteomics.

[58]  A. Gutiérrez-Adán,et al.  Histone Modifications at the Blastocyst Axin1Fu Locus Mark the Heritability of In Vitro Culture-Induced Epigenetic Alterations in Mice1 , 2010, Biology of reproduction.

[59]  K. Osteen,et al.  Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. , 2011, Reproductive toxicology.

[60]  J. David Sweatt,et al.  Epigenetic Mechanisms in Cognition , 2011, Neuron.

[61]  A. Paoloni-Giacobino,et al.  The role of DMDs in the maintenance of epigenetic states , 2006, Cytogenetic and Genome Research.

[62]  B. Walker Tumors of female offspring of mice exposed prenatally to diethylstilbestrol. , 1984, Journal of the National Cancer Institute.

[63]  I. Weaver,et al.  The Transcription Factor Nerve Growth Factor-Inducible Protein A Mediates Epigenetic Programming: Altering Epigenetic Marks by Immediate-Early Genes , 2007, The Journal of Neuroscience.

[64]  K. Kendler Twin studies of psychiatric illness: an update. , 2001, Archives of general psychiatry.

[65]  V. Rakyan,et al.  Transgenerational inheritance of epigenetic states at the murine AxinFu allele occurs after maternal and paternal transmission , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[66]  Julie A. Law,et al.  Establishing, maintaining and modifying DNA methylation patterns in plants and animals , 2010, Nature Reviews Genetics.

[67]  N. Youngson,et al.  Transgenerational epigenetic effects. , 2008, Annual review of genomics and human genetics.

[68]  R. Newbold,et al.  Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. , 2006, Endocrinology.

[69]  B. Cairns,et al.  Distinctive Chromatin in Human Sperm Packages Genes for Embryo Development , 2009, Nature.

[70]  L. Tsai,et al.  Targeting the correct HDAC(s) to treat cognitive disorders. , 2010, Trends in pharmacological sciences.

[71]  Emma Y. Wu,et al.  Antidepressant Actions of Histone Deacetylase Inhibitors , 2009, The Journal of Neuroscience.

[72]  E. Rolls,et al.  Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy , 2012, Nature Reviews Drug Discovery.

[73]  S. Krawetz Paternal contribution: new insights and future challenges , 2005, Nature Reviews Genetics.

[74]  Michael K. Skinner,et al.  Epigenetic Transgenerational Actions of Vinclozolin on Promoter Regions of the Sperm Epigenome , 2010, PloS one.

[75]  W. Yeung,et al.  miR-135A Regulates Preimplantation Embryo Development through Down-Regulation of E3 Ubiquitin Ligase Seven in Absentia Homolog 1A (SIAH1A) Expression , 2011, PloS one.

[76]  J. Ohgane,et al.  Neonatal exposure to diethylstilbestrol alters expression of DNA methyltransferases and methylation of genomic DNA in the mouse uterus. , 2009, Endocrine journal.

[77]  Robert Blelloch,et al.  Small RNAs in early mammalian development: from gametes to gastrulation , 2011, Development.

[78]  M. Dawson,et al.  Cancer Epigenetics: From Mechanism to Therapy , 2012, Cell.

[79]  Jason H. Moore,et al.  Missing heritability and strategies for finding the underlying causes of complex disease , 2010, Nature Reviews Genetics.

[80]  R. Kodell,et al.  Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[81]  P. Hájková Epigenetic reprogramming in the germline: towards the ground state of the epigenome , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[82]  J. Connelly,et al.  Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. , 2012, Endocrinology.

[83]  Antoine H. F. M. Peters,et al.  Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa , 2010, Nature Structural &Molecular Biology.

[84]  S. Krawetz,et al.  The sperm nucleus: chromatin, RNA, and the nuclear matrix. , 2011, Reproduction.

[85]  David I. K. Martin,et al.  Epigenetic inheritance at the agouti locus in the mouse , 1999, Nature Genetics.

[86]  Holger Russig,et al.  Influence of Early Stress on Social Abilities and Serotonergic Functions across Generations in Mice , 2011, PloS one.

[87]  I. Mansuy,et al.  Comprehensive mapping of post-translational modifications on synaptic, nuclear, and histone proteins in the adult mouse brain. , 2009, Journal of proteome research.

[88]  Alex Mesoudi,et al.  Beyond DNA: integrating inclusive inheritance into an extended theory of evolution , 2011, Nature Reviews Genetics.

[89]  Michael K. Skinner,et al.  Transgenerational Epigenetic Programming of the Brain Transcriptome and Anxiety Behavior , 2008, PloS one.

[90]  J. Curley,et al.  Parent-of-origin and trans-generational germline influences on behavioral development: the interacting roles of mothers, fathers, and grandparents. , 2010, Developmental psychobiology.

[91]  P. Gluckman,et al.  Developmental origins of metabolic disease: life course and intergenerational perspectives , 2010, Trends in Endocrinology & Metabolism.

[92]  W. Reik,et al.  Genomic imprinting: parental influence on the genome , 2001, Nature Reviews Genetics.

[93]  J. McLachlan,et al.  Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. , 1997, Cancer research.

[94]  Michael J Meaney,et al.  Epigenetic programming by maternal behavior , 2004, Nature Neuroscience.

[95]  P. Gounon,et al.  RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse , 2006, Nature.

[96]  Shaomin Li,et al.  Transgenerational Rescue of a Genetic Defect in Long-Term Potentiation and Memory Formation by Juvenile Enrichment , 2009, The Journal of Neuroscience.

[97]  C. Plass,et al.  Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[98]  K. Sinclair,et al.  Assisted reproductive technology, epigenetics, and long-term health: a developmental time bomb still ticking. , 2009, Seminars in reproductive medicine.