Epigenetics, autism spectrum, and neurodevelopmental disorders

Abstract

Epigenetic marks are modifications of DNA and histones. They are considered to be permanent within a single cell during development, and are heritable across cell division. Programming of neurons through epigenetic mechanisms is believed to be critical in neural development. Disruption or alteration in this process causes an array of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Recent studies have provided evidence for an altered epigenetic landscape in ASDs and demonstrated the central role of epigenetic mechanisms in their pathogenesis. Many of the genes linked to the ASDs encode proteins that are involved in transcriptional regulation and chromatin remodeling. In this review we highlight selected neurodevelopmental disorders in which epigenetic dysregulation plays an important role. These include Rett syndrome, fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, and Kabuki syndrome. For each of these disorders, we discuss how advances in our understanding of epigenetic mechanisms may lead to novel therapeutic approaches.

Fig. 1

Diagram of the imprinted maternal and paternal chromosome 15q11-q13 regions containing Prader–Willi/Angelman Syndrome (PWS–AS) locus. This locus controls maternal and paternal specific expression of (A) protein-coding genes ubiquitin protein ligase E3A (UBE3A) and SNURF/SNRPN = SNRPN upstream reading frame / small nuclear ribonucleoprotein polypeptide N (green); (B) long noncoding RNA (lncRNA) HBII-85, imprinted in Prader-Willi (IPW), HBII-52 (blue); and (C) UBE3A-antisense RNA transcript (ATS) (0.5–1.0 Mb in length) that overlaps the UBE3A gene. The PWS/AS imprinting centers (AS-IC and PWS-IC) have parent specific epigenetic marks that regulate gene expression. During development, the AS-IC (open circle) establishes and maintains the PWS-IC on the maternal chromosome. Methylation at PWS-IC (pink triangles) on the maternal chromosome suppresses expression of genes downstream of the PWS-IC center (red bar). On the paternal chromosome, differential methylation of PWS-IC results in paternal expression of lncRNAs, including the UBE3A-ATS, which represses UBE3A gene expression (red bar) [–29]

Fig. 2

The FMR1 gene contains a promoter region (violet box) flanked by an upstream CpG island and a <45-repeat CGG tract (blue oval), which is followed by the transcription start site. Recognized domains include a nuclear localization signal (NLS) , K-homology domains (KH1 and KH2) , an arginine–glycine–glycine box (RGG), and a nuclear export signal (NES). In normal patients, in the FMR1 promoter region, there are high levels of histone acetylation and H3K4 methylation resulting in a euchromatic state for FMR1 gene expression. In fragile X syndrome (FXS), the presence of >200 CGG repeats induces methylation of histones (H3K9) in the promoter region. This results in DNA methylation of promoter and the upstream CpG island resulting in a heterochromatized state and FMR1 inactivation

Fig. 3

a Schematic diagram of MeCP2 domain structure and protein interactions. mCpG binding domain (MBD) [amino acids (aa) 78–162]; transcriptional repression domain (TRD) (aa 207–310) the transcription repressor domain. There are 2 nuclear localization signals (NLS), 1 between the MBD and TRD, and the other within the TRD. Three AT-hook domains have been identified: AT-hook 1 (aa 185–194), AT-hook 2 (aa 265–272) in TRD domain, and AT-hook 3 in the C-terminus. Many factors interact with these MeCP2 domains mediating specific MeCP2 functions like chromatin structure modulation, gene activation, and gene repression. b Model of the dual role of MeCp2 as a transcriptional repressor and activator. MeCp2 competes with histone H1 for sites within linker DNA resulting in a heterochromatin structure and transcriptional repression. In this process, MeCP2 interacts with 5mC = 5-methylcytosine and ATRX = alpha thalassemia / mental retardation X-linked through its MDB domain, while the AT-hook domain in the TRD interacts with AT-rich DNA. MeCP2 bound to 5mC recruits transcription repressors and co-repressors [mSin3, histone deacetylase (HDAC)] resulting in transcriptional down-regulation. When MeCP2 binds hydroxymethyl cytosine (5hmC), it recruits transcription co-activators such as cycline adenosine monophosphate response element-binding protein (CREB), to activate target gene transcription. 5mCpG = 5-methyl cytosine phospho guanosine; coREST = corepressor of REST (RE1 silencing transcription factor); CREB = cAMP response element-binding protein; RNA Pol II = RNA polymerase II