Neuropharmacology Available online 11 December 2012

Invited review

An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy

Mark J. Millan

Unit for Research and Discovery in Neuroscience, IDR Servier, 125 chemin de ronde, 78290 Croissy sur Seine, Paris, France http://dx.doi.org/10.1016/j.neuropharm.2012.11.015, How to Cite or Link Using DOI Permissions & Reprints

Highlights
Neurodevelopmental disorders like autism involve abnormal development of brain. Some rare disorders are monogenetic, like Fragile X, but most are polygenetic. Certain involve environmental factors, like pre-natal infection or early life trauma. Both genetic and environmental factors disrupt epigenetic control of gene expression. Processes include DNA and histone methylation, and miRNA control of mRNA translation.

Abstract
Neurodevelopmental disorders (NDDs) are characterized by aberrant and delayed early-life development of the brain, leading to deficits in language, cognition, motor behaviour and other functional domains, often accompanied by somatic symptoms. Environmental factors like perinatal infection, malnutrition, trauma and poor parental care increase the risk of the heterogeneous, multifactorial and polygenic disorders, autism and schizophrenia. Conversely, discrete genetic anomalies are involved in Down, Rett and Fragile X syndromes, tuberous sclerosis and neurofibromatosis, the less familiar PhelanMcDermid, Sotos, Kleefstra, CoffinLowry and ATRX syndromes, and the disorders of imprinting, Angelman and Prader Willi syndromes. NDDs have been termed synaptopathies in reference to structural and functional disturbance of synaptic plasticity, several involve abnormal Ras-Kinase signalling (rasopathies), and many are characterized by disrupted cerebral connectivity and an imbalance between excitatory and inhibitory transmission. However, at a different level of integration, NDDs are accompanied by aberrant epigenetic regulation of processes critical for normal and orderly development of the brain. Epigenetics refers to potentially-heritable (by mitosis and/or meiosis) mechanisms controlling gene expression without changes in DNA sequence. In certain NDDs, prototypical epigenetic processes of DNA methylation and covalent histone marking are impacted. Conversely, others involve anomalies in chromatinmodelling, mRNA splicing/editing, mRNA translation, ribosome biogenesis and/or the regulatory actions of small nucleolar RNAs and micro-RNAs. Since epigenetic mechanisms are modifiable, this raises the hope of novel therapy, though questions remain concerning efficacy and safety. The above issues are critically surveyed in this review, which advocates a broad-based epigenetic framework for understanding and ultimately treating a diverse assemblage of NDDs (epigenopathies) lying at the interface of genetic, developmental and environmental processes. This article is part of a Special Issue entitled Neurodevelopment Disorder.

Epigenetic mechanisms from gene to protein: a complex, non-linear and eventful journey.
(See Figure 1 below)

Fig. 1. Epigenetic mechanisms from gene to protein: a complex, non-linear and eventful journey. Schematic representation of key epigenetic mechanisms modulating gene expression in the absence of alterations in DNA sequence. DNA and histones (chromatin) are packaged into nucleosomes with DNA wound around complexes of 8 histones (one H3-H4 tetramer and two H2A-2B dimers). As outlined in the text, special chromatin-modelling proteins control the organization and composition of nucleosomes. Dynamically-regulated DNA methylation, which represses transcription, mainly occurs at Cytosinephosphate Guanine (CpG) rich islands wherein most promoters are embedded. Histones, principally their tails, are subject to a complex and interacting pattern of posttranscriptional modifications controlling transcription (Table 1): gene expression is either activated of repressed dependent upon the mark, the residue affected and its epigenetic environment (other marks etc). The major modifications are shown, including acetylation (at lysine residues, and resulting in chromatin decondensation and transcriptional activation) methylation (lysine or residues arginines, activation or repression) and phosphorylation (activation), though other marks (not shown) of less evident pertinence to NDDs are also imposed (see text). Enzymes responsible for writing and erasing histone and DNA marks are indicated in Table 1. The Figure is based upon the fate of protein-coding genes, but non protein-coding stretches of RNA with regulatory (epigenetic) functions

are themselves under the control of promoters and may epigenetically be processed. Thus, in addition to proteins, the chromatin code controls the generation of intergenic sequences encoding microRNAs (miRNAs) and lncRNAs (long non-coding RNAs) which influence (usually suppress) the translation of mRNAs. Prior to translation, mRNA is subject to splicing (for protein-coding genes with introns) and, in some cases, Adenosine-to-Inosine editing, processes modulated by snoRNAs (small nucleolar RNAs). SnoRNAs also control the processing or rRNA prior to incorporation into ribosomes (not shown). Ribosomes classically effect mRNA translation by virtue of their peptidyltransferase activity and, together with chaperone proteins, determine proteinfolding and the 3D configuration of exiting proteins. While chromatin marking occurs in the nucleus, epigenetic processing of mRNA occurs in discrete compartments like dendritic spines and can be regulated locally (Bramham and Wells, 2007). Post-epigenetically, proteins are subject to chemical modification which will influence their conformation, functional status and interacting protein partners. See text for further details

Keywords

Epigenopathy; Histone; Chromatin; Methylation; Acetylation; MiRNA; SnoRNA; Noncoding RNA; Autism; Schizophrenia

Abbreviations

ADHD, Attention-Deficit Hyperactivity Disorder; AKT, Atypical protein kinase; AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Arc, Activity-regulated cytoskeleton-associated protein; ASD, Autism-spectrum disorder; ATRX, SWI2/SNF2 DNA ATP-dependent Helicase II; BDNF, Brain-derived neurotrophic factor; CaMKII, Calcium/calmodulin-dependent kinase II; CAPS, Calcium-dependent activator of protein secretion; CBP, CREB-binding protein; CHARGE, Coloboma, Heart malformation, choanal Atresia, Retardation of growth and development, Genital anomalies, and Ear anomalies; CpG, CytosinephosphateGuanosine;

CNV, Copy Number Variant; CREB, cAMP response element binding; DGCR, DiGeorge Critical Region; DISC, Disrupted in schizophrenia; DNMT, DNA methyltransferase; DYRK, Dual-specificity tyrosine phosphorylation-regulated kinase; eIF, Elongation initiation factor; ERK, Extracellular Regulated Kinase; FMRP, Fragile X Mental Retardation Protein; GAD, GABA decarboxylase; Gadd, Growth arrest and DNA damage; GLP, G9a-like protein; HPA, HypothalamusPituitaryAdrenocorticotrophic; ICF, Immunodeficiency, Centeromeric region instability and Facial anomalies; ID, Intellectual disability; JARID1C, Jumonji AT-rich Interactive Domain 1C; KHDM, Lysine histone demethylase; KHMT, Lysine histone methyltransferase; LncRNA, Long non-coding RNA; LTD, Long-term depression; LTP, Long-term potentiation; MAP-Kinase, Mitogen-activated protein kinase; MDBP, Methyl-DNA binding protein; MeCP2, Methyl-CpG-binding protein2; mGluR, Metabotropic glutamate receptor; MiRNAs, MicroRNA; MSK, Mitogen- and stress-activated protein kinase; MTOR, Mammalian target of rapamycin; NDD, Neurodevelopmental disorder; NMDA, N-Methyl-d-Aspartate; NSD, Nuclear receptor SET-domain-containing protein; PHD, Plant homeodomain; PHF8, Plant homeodomain finger protein 8; PI3-Kinase, Phosphatidyl inositol3-Kinase; PiRNA, Piwi-interacting RNA; PrPc, Cellular prion protein; PTEN, Phosphatase and Tensin Homologue; PW/AS-IC, PraderWilli/Angelman imprinting centre; REST, Repressor Element 1-silencing transcription factor; RHMT, Arginine histone methyltransferase; RSK2, P90 ribosomal S6 kinase 2; SHANK3, SH3 and multiple ankyrin repeat domain 3; SnoRNA, Small nucleolar RNA; SNP, Single nucleotide polymorphism; TGI, Transgenerational inheritance; XLMR, X-linked mental retardation