Epigenetics In Development

Advances in Autism Research
April 2010

Appreciation of epigenetic phenomena (explained here) is increasing. Not only may epigenetic changes be relevant to some and perhaps many cases of autism (1-13) but also, epigenetic encodings etiologically significant in specific individuals with autism may be why so many gene-search studies have found only soft (though often instructive) associations. Epigenetic changes can be induced by pollutants (eg, 14-19). The Pubmed search epigenet* AND autis* on March 19, 2010, generated 91 citations (eg, 20-30). A goodly number of reviews about epigenetics are free online (eg, 31-43).

1. Epigenetics in development
Kiefer JC.
University of Utah
Dev Dyn. 2007 Apr;236(4):1144-56.
http://www3.interscience.wiley.com/cgi-bin/fulltext/114123018/PDFSTART

It has become increasingly evident in recent years that development is under epigenetic control. Epigenetics is the study of heritable changes in gene function that occur independently of alterations to primary DNA sequence. The best-studied epigenetic modifications are DNA methylation, and changes in chromatin structure by histone modifications, and histone exchange. An exciting, new chapter in the field is the finding that long-distance chromosomal interactions also modify gene expression. Epigenetic modifications are key regulators of important developmental events, including X-inactivation, genomic imprinting, patterning by Hox genes and neuronal development. This primer covers these aspects of epigenetics in brief, and features an interview with two epigenetic scientists.

2. Epigenetic principles and mechanisms underlying nervous system functions in health and disease
Mehler MF.
Albert Einstein College of Medicine
Prog Neurobiol. 2008 Dec 11;86(4):305-41. Epub 2008 Oct 17.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2636693/pdf/nihms83673.pdf

Epigenetics and epigenomic medicine encompass a new science of brain and behavior that are already providing unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. Epigenetic mechanisms include DNA methylation, histone modifications, nucleosome repositioning, higher order chromatin remodeling, non-coding RNAs, and RNA and DNA editing. RNA is centrally involved in directing these processes, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. This transcriptional state can be modified not only by internal and external cues affecting gene expression and post-transcriptional processing, but also by RNA and DNA editing through activity-dependent intracellular transport and modulation of RNAs and RNA regulatory supercomplexes, and through trans-neuronal and systemic trafficking of functional RNA subclasses. These integrated processes promote dynamic reorganization of nuclear architecture and the genomic landscape to modulate functional gene and neural networks with complex temporal and spatial trajectories. Epigenetics represents the long sought after molecular interface mediating gene-environmental interactions during critical periods throughout the lifecycle. The discipline of environmental epigenomics has begun to identify combinatorial profiles of environmental stressors modulating the latency, initiation and progression of specific neurological disorders, and more selective disease biomarkers and graded molecular responses to emerging therapeutic interventions. Pharmacoepigenomic therapies will promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cell fate decisions, targeted tissue remodeling and restoration of neural network integrity, plasticity and connectivity.

3. Temporal and epigenetic regulation of neurodevelopmental plasticity
Allen ND.
Cardiff University
Philos Trans R Soc Lond B Biol Sci. 2008 Jan 12;363(1489):23-38.
http://rstb.royalsocietypublishing.org/content/363/1489/23.long

The anticipated therapeutic uses of neural stem cells depend on their ability to retain a certain level of developmental plasticity. In particular, cells must respond to developmental manipulations designed to specify precise neural fates. Studies in vivo and in vitro have shown that the developmental potential of neural progenitor cells changes and becomes progressively restricted with time. For in vitro cultured neural progenitors, it is those derived from embryonic stem cells that exhibit the greatest developmental potential. It is clear that both extrinsic and intrinsic mechanisms determine the developmental potential of neural progenitors and that epigenetic, or chromatin structural, changes regulate and coordinate hierarchical changes in fate-determining gene expression. Here, we review the temporal changes in developmental plasticity of neural progenitor cells and discuss the epigenetic mechanisms that underpin these changes. We propose that understanding the processes of epigenetic programming within the neural lineage is likely to lead to the development of more rationale strategies for cell reprogramming that may be used to expand the developmental potential of otherwise restricted progenitor populations.

4. Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life?
Burdge GC, Hanson MA, Slater-Jefferies JL, Lillycrop KA.
University of Southampton
Br J Nutr. 2007 Jun;97(6):1036-46. Epub 2007 Mar 7.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211525/pdf/nihms-1429.pdf

There is considerable evidence for the induction of different phenotypes by variations in the early life environment, including nutrition, which in man is associated with a graded risk of metabolic disease; fetal programming. It is likely that the induction of persistent changes to tissue structure and function by differences in the early life environment involves life-long alterations to the regulation of gene transcription. This view is supported by both studies of human subjects and animal models. The mechanism which underlies such changes to gene expression is now beginning to be understood. In the present review we discuss the role of changes in the epigenetic regulation of transcription, specifically DNA methylation and covalent modification of histones, in the induction of an altered phenotype by nutritional constraint in early life. The demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life.

5. The role of epigenetics in mental disorders
Peedicayil J.
Indian J Med Res. 2007 Aug;126(2):105-11.
http://www.icmr.nic.in/ijmr/2007/august/0804.pdf

It is well established that the idiopathic mental disorders have a genetic basis. Yet, genetic mapping has not definitively identified any genetic mutation or polymorphism underlying these disorders. This review discusses the role of epigenetics in the pathogenesis of the idiopathic mental disorders. Epimutations and epigenetic polymorphisms are emphasized as being an interface between the genes underlying the idiopathic mental disorders and the environment. Psychosocial factors are described as important environmental factors involved in the pathogenesis of the idiopathic mental disorders, modifying the underlying genes by epigenetic mechanisms. Epigenetic strategies to identify the genes underlying the idiopathic mental disorders are described and the available molecular evidence supporting an epigenetic pathogenesis for these disorders is discussed. It also discusses the role of epigenetic factors in the pathogenesis of neuropsychiatric disorders and the relevance of the new therapeutic option, epigenetic therapy, in treating the idiopathic mental disorders and the neuropsychiatric disorders.

6. Different epigenetic layers engage in complex crosstalk to define the epigenetic state of mammalian rRNA genes
Grummt I.
German Cancer Research Center, Heidelberg
Hum Mol Genet. 2007 Apr 15;16 Spec No 1:R21-7.
http://hmg.oxfordjournals.org/cgi/reprint/16/R1/R21

Eukaryotic cells contain several hundred ribosomal RNA (rRNA) genes (rDNA), a fraction of them being silenced by epigenetic mechanisms. The presence of two epigenetically distinct states of rRNA genes provides a unique opportunity to decipher the molecular mechanisms that establish the euchromatic, i.e. transcriptionally active, and the heterochromatic, i.e. transcriptionally silent, state of rDNA. This article summarizes our knowledge of the epigenetic mechanisms that control rDNA transcription and emphasizes how DNA methyltransferases and histone-modifying enzymes work in concert with chromatin-remodeling complexes and RNA-guided mechanisms to establish a specific chromatin structure that defines the transcriptional state of rRNA genes. These studies exemplify the mutual dependence and complex crosstalk among different epigenetic players in the alteration of the chromatin structure during the process of gene activation or silencing.

7. Epigenetic mechanisms regulating fate specification of neural stem cells
Namihira M, Kohyama J, Abematsu M, Nakashima K.
Nara Institute of Science and Technology
Philos Trans R Soc Lond B Biol Sci. 2008 Jun 27;363(1500):2099-109.
http://rstb.royalsocietypublishing.org/content/363/1500/2099.long

Neural stem cells (NSCs) possess the ability to self-renew and to differentiate along neuronal and glial lineages. These processes are defined by the dynamic interplay between extracellular cues including cytokine signalling and intracellular programmes such as epigenetic modification. There is increasing evidence that epigenetic mechanisms involving, for example, changes in DNA methylation, histone modification and non-coding RNA expression are closely associated with fate specification of NSCs. These epigenetic alterations could provide coordinated systems for regulating gene expression at each step of neural cell differentiation. Here we review the roles of epigenetics in neural fate specification in the mammalian central nervous system.

8. Epigenetics in the nervous system
Jiang Y et al.
University of Massachusetts Medical School
J Neurosci. 2008 Nov 12;28(46):11753-9.
http://www.jneurosci.org/cgi/content/full/28/46/11753

It is becoming increasingly clear that epigenetic modifications are critical factors in the regulation of gene expression. With regard to the nervous system, epigenetic alterations play a role in a diverse set of processes and have been implicated in a variety of disorders. Gaining a more complete understanding of the essential components and underlying mechanisms involved in epigenetic regulation could lead to novel treatments for a number of neurological and psychiatric conditions.

9. Epigenetic regulation of cytokine gene expression in T lymphocytes
Lee CG, Sahoo A, Im SH.
Yonsei Med J. 2009 Jun 30;50(3):322-30. Epub 2009 Jun 23.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703752/pdf/ymj-50-322.pdf

The developmental program of T helper and regulatory T cell lineage commitment is governed by both genetic and epigenetic mechanisms. The principal events, signaling pathways and the lineage determining factors involved have been extensively studied in the past ten years. Recent studies have elucidated the important role of chromatin remodeling and epigenetic changes for proper regulation of gene expression of lineage-specific cytokines. These include DNA methylation and histone modifications in epigenomic reprogramming during T helper cell development and effector T cell functions. This review discusses the basic epigenetic mechanisms and the role of transcription factors for the differential cytokine gene regulation in the T helper lymphocyte subsets.

10. How are T(H)1 and T(H)2 effector cells made?
Amsen D, Spilianakis CG, Flavell RA.
University of Amsterdam, Amsterdam, The Netherlands.
Curr Opin Immunol. 2009 Apr;21(2):153-60. Epub 2009 Apr 15.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695256/pdf/nihms116995.pdf

Differentiation of T(H)1 and T(H)2 effector cells proceeds through several phases: First, naïve CD4(+) precursor cells are instructed to differentiate as appropriate to optimally fight the infectious threat encountered. This process is governed by the IL12 and IL4 cytokines, as well as by signaling through the Notch receptor. In response to these signals, transcription is initiated of lineage specific cytokine genes including the Ifngamma and Il4 genes as well as of genes encoding transcriptional regulators, such as T-bet and Gata3. The respective differentiation programs are reinforced by both positive and negative feedback mechanisms. Furthermore, epigenetic modifications of the lineage specific genes result in the emergence of regulatory elements, which control high level lineage restricted expression by both intrachromosomal and interchromosomal associations. Together, these mechanisms ensure stable inheritance of the differentiated fate in the numerous progeny of the original naïve CD4(+) T cells.

11. Chromatin-level regulation of the IL10 gene in T cells
Im SH, Hueber A, Monticelli S, Kang KH, Rao A.
J Biol Chem. 2004 Nov 5;279(45):46818-25.
http://www.jbc.org/content/279/45/46818.long

The immunoregulatory cytokine interleukin 10 (IL-10) modulates the function of diverse immune and non-immune cells. Here, we examine the chromatin structural changes associated with IL10 gene transcription by naive and differentiated murine T cells. Naive T cells lack DNase I hypersensitive (HS) sites in the vicinity of the IL10 gene, whereas differentiated T cells display a strong 3' constitutive HS site as well as several inducible sites. The majority of HS sites map to regions that are strongly conserved in sequence between mouse and human genomes. In committed Th1 cells, the mechanism of IL10 gene silencing is associated with the development of repressive histone modifications near the IL10 promoter and also near intronic hypersensitive regions of the IL10 gene. Our results constitute the first report of chromatin structural differences within the IL10 gene in differentiated Th1 and Th2 cells and emphasize the surprising diversity of mechanisms used to regulate cytokine gene expression at the chromatin level.

12. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation
Chen Z, Laurence A, O'Shea JJ.
National Institutes of Health
Semin Immunol. 2007 Dec;19(6):400-8.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2323678/pdf/nihms42180.pdf

The discovery of a new lineage of helper T cells that selectively produces interleukin (IL)-17 has provided exciting new insights into immunoregulation, host defense and the pathogenesis of autoimmune diseases. Additionally, the discovery of this T cell subset has offered a fresh look at how the complexity of selective regulation of cytokine gene expression might relate to lineage commitment, terminal differentiation and immunologic memory. Information continues to accumulate on factors that regulate Th17 differentiation at a rapid pace and a few lessons have emerged. Like other lineages, Th17 cells preferentially express a transcription factor, retinoic acid-related orphan receptor (ROR)gammat, whose expression seems to be necessary for IL-17 production. In addition, signals from the T-cell receptor are a critical aspect of controlling IL-17 production and the transcription factor nuclear factor of activated T cells (NFATs) appears to be another important regulator. IL-6, IL-21 and IL-23 are all cytokines that activate the transcription factor STAT3, which has been established to be necessary for multiple aspects of the biology of Th17 cells. Similarly, TGFbeta-1 is important for the differentiation of murine Th17 cells and inducible regulatory T cells (iTregs), but how it exerts its effect on IL-17 gene transcription is unknown and there are data indicating TGFbeta-1 is not required for human Th17 differentiation. The extent to which Th17 cells represent terminally differentiated cells or whether they retain plasticity and can develop into another lineage such as IFNgamma secreting Th1 cells is also unclear. Precisely how cytokines produced by this lineage are selectively expressed and selectively extinguished through epigenetic modifications is an area of great importance, but considerable uncertainty.

13. Epigenetic modifications in rheumatoid arthritis
Strietholt S, Maurer B, Peters MA, Pap T, Gay S.
Institute of Experimental Musculoskeletal Medicine, Germany
Arthritis Res Ther. 2008;10(5):219. Epub 2008 Oct 10.
http://arthritis-research.com/content/pdf/ar2500.pdf

Over the last decades, genetic factors for rheumatoid diseases like the HLA haplotypes have been studied extensively. However, during the past years of research, it has become more and more evident that the influence of epigenetic processes on the development of rheumatic diseases is probably as strong as the genetic background of a patient. Epigenetic processes are heritable changes in gene expression without alteration of the nucleotide sequence. Such modifications include chromatin methylation and post-translational modification of histones or other chromatin-associated proteins. The latter comprise the addition of methyl, acetyl, and phosphoryl groups or even larger moieties such as binding of ubiquitin or small ubiquitin-like modifier. The combinatory nature of these processes forms a complex network of epigenetic modifications that regulate gene expression through activation or silencing of genes. This review provides insight into the role of epigenetic alterations in the pathogenesis of rheumatoid arthritis and points out how a better understanding of such mechanisms may lead to novel therapeutic strategies.

14.Hypothesis: a unifying mechanism for nutrition and chemicals as lifelong modulators of DNA hypomethylation.

Lee DH, Jacobs DR Jr, Porta M.
Environ Health Perspect. 2009 Dec;117(12):1799-802

15. The developmental origins of asthma: does epigenetics hold the key?
Shaheen SO, Adcock IM.
Am J Respir Crit Care Med. 2009 Oct 15;180(8):690-1.

16. Relationship between environmental exposures in children and adult lung disease: The case for outdoor exposures.
Soto-Martinez M, Sly P.
Chron Respir Dis. 2009 Oct 9. [Epub ahead of print]

17. Environmental influences on epigenetic profiles.
Suter MA, Aagaard-Tillery KM.
Semin Reprod Med. 2009 Sep;27(5):380-90.

19.Epigenetics and environmental chemicals.

Baccarelli A, Bollati V.
Curr Opin Pediatr. 2009 Apr;21(2):243-51.

20.Genetic factors and epigenetic factors for autism: endoplasmic reticulum stress and impaired synaptic function.

Momoi T, Fujita E, Senoo H, Momoi M.
Cell Biol Int. 2009 Dec 16;34(1):13-9.

21. Advancing paternal age is associated with deficits in social and exploratory behaviors in the offspring: a mouse model.
Smith RG, Kember RL, Mill J, Fernandes C, Schalkwyk LC, Buxbaum JD, Reichenberg A.
PLoS One. 2009 Dec 30;4(12):e8456.

22. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases.
Lahiri DK, Maloney B, Zawia NH.
Mol Psychiatry. 2009 Nov;14(11):992-1003.

23. Defective oxytocin function: a clue to understanding the cause of autism?
Gurrieri F, Neri G.
BMC Med. 2009 Oct 22;7:63.

24. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism.
Gregory SG et al.
BMC Med. 2009 Oct 22;7:62.

25. Understanding and determining the etiology of autism.
Currenti SA.
Cell Mol Neurobiol. 2010 Mar;30(2):161-71.

26. Investigating epigenetic influences on seizure disposition.
Gilby KL.
Can J Neurol Sci. 2009 Aug;36 Suppl 2:S78-81.

27. Autism, fever, epigenetics and the locus coeruleus.
Mehler MF, Purpura DP.
Brain Res Rev. 2009 Mar;59(2):388-92.

28. Epigenetic regulation in human brain-focus on histone lysine methylation.
Akbarian S, Huang HS.
Biol Psychiatry. 2009 Feb 1;65(3):198-203.

29. Minor physical anomalies in autism: a meta-analysis.
Ozgen HM, Hop JW, Hox JJ, Beemer FA, van Engeland H.
Mol Psychiatry. 2010 Mar;15(3):300-7.

30. Immunologic and neurodevelopmental susceptibilities of autism.
Pessah IN, Seegal RF, Lein PJ, LaSalle J, Yee BK, Van De Water J, Berman RF.

Neurotoxicology. 2008 May;29(3):532-45.

31.Epigenetics: a molecular link between environmental factors and type 2 diabetes.

Ling C, Groop L.
Diabetes. 2009 Dec;58(12):2718-25.

32.Epigenetics: definition, mechanisms and clinical perspective.
Dupont C, Armant DR, Brenner CA.
Semin Reprod Med. 2009 Sep;27(5):351-7.

33.Epigenetics in the placenta.
Maccani MA, Marsit CJ.
Am J Reprod Immunol. 2009 Aug;62(2):78-89.

34. Decoding the epigenetic language of neuronal plasticity.
Borrelli E, Nestler EJ, Allis CD, Sassone-Corsi P.
Neuron. 2008 Dec 26;60(6):961-74.

35. Autism, fever, epigenetics and the locus coeruleus.
Mehler MF, Purpura DP.
Brain Res Rev. 2009 Mar;59(2):388-92.

36. Epigenetics in the nervous system.
Jiang Y et al.
J Neurosci. 2008 Nov 12;28(46):11753-9.

37. Epigenetic mechanisms in mammals.
Kim JK, Samaranayake M, Pradhan S.
Cell Mol Life Sci. 2009 Feb;66(4):596-612.

38. Epigenetic principles and mechanisms underlying nervous system functions in health and disease.
Mehler MF.
Prog Neurobiol. 2008 Dec 11;86(4):305-41.

39. Epigenetic regulation in human brain-focus on histone lysine methylation.
Akbarian S, Huang HS.
Biol Psychiatry. 2009 Feb 1;65(3):198-203.

40. Gene-environment interactions and epigenetic basis of human diseases.
Liu L, Li Y, Tollefsbol TO.
Curr Issues Mol Biol. 2008;10(1-2):25-36.

41. Epigenetic regulation of vascular endothelial gene expression.
Matouk CC, Marsden PA.
Circ Res. 2008 Apr 25;102(8):873-87.

42. Epigenetic mechanisms regulating fate specification of neural stem cells.
Namihira M, Kohyama J, Abematsu M, Nakashima K.
Philos Trans R Soc Lond B Biol Sci. 2008 Jun 27;363(1500):2099-109.

43. Epigenetics and its implications for behavioral neuroendocrinology.

Crews D.
Front Neuroendocrinol. 2008 Jun;29(3):344-57.

his document prepared by
Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 2010