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      Epigenetics studies of fetal alcohol spectrum disorder: where are we now?

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          Abstract

          Adverse in utero events can alter the development and function of numerous physiological systems, giving rise to lasting neurodevelopmental deficits. In particular, data have shown that prenatal alcohol exposure can reprogram neurobiological systems, altering developmental trajectories and resulting in increased vulnerability to adverse neurobiological, behavioral and health outcomes. Increasing evidence suggests that epigenetic mechanisms are potential mediators for the reprogramming of neurobiological systems, as they may provide a link between the genome, environmental conditions and neurodevelopmental outcomes. This review outlines the current state of epigenetic research in fetal alcohol spectrum disorder, highlighting the role of epigenetic mechanisms in the reprogramming of neurobiological systems by alcohol and as potential diagnostic tools for fetal alcohol spectrum disorder. We also present an assessment of the current limitations in studies of prenatal alcohol exposure, and highlight the future steps needed in the field.

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          Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

          Ruthie Amir, Ignatia B Van den Veyver, Mimi Wan … (1999)
          Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
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            Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters

            Alika Maunakea, Raman P. Nagarajan, Mikhail Bilenky … (2010)
            While the methylation of DNA in 5′ promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear 1–5 . In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5′ CpG island (CGI) promoters, while a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences 5–10 . Tissue-specific intragenic methylation might reduce, 3 or, paradoxically, enhance transcription elongation efficiency 1,2,4,5 . Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes 11–15 . To investigate the role of intragenic methylation, we generated a map of DNA methylation from human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were revealed to be in intragenic and intergenic regions, while less than 3% of CpG islands in 5′ promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters 16 . The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus 17,18 and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
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              Chromatin structure: a repeating unit of histones and DNA.

              R D Kornberg (1974)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Epigenomics
                Journal ID (iso-abbrev): Epigenomics
                Journal ID (publisher-id): EPI
                Title: Epigenomics
                Publisher: Future Medicine Ltd (London, UK )
                ISSN (Print): 1750-1911
                ISSN (Electronic): 1750-192X
                Publication date (Print): March 2017
                Publication date (Electronic): 17 February 2017
                Volume: 9
                Issue: 3
                Pages: 291-311
                Affiliations
                [1 ]Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
                [2 ]Department of Cellular & Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
                [3 ]Human Early Learning Partnership, University of British Columbia, Vancouver, British Columbia, Canada
                Author notes
                *Author for correspondence: msk@ 123456cmmt.ubc.ca
                Article
                DOI: 10.2217/epi-2016-0163
                PMC ID: 5549650
                PubMed ID: 28234026
                SO-VID: 9020f36c-233c-4316-9b73-9bfdefc4e6ed
                Copyright © © 2017 Michael S. Kobor
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License

                History
                Date received : 22 October 2016
                Date accepted : 19 December 2016
                Categories
                Subject: Perspective

                Keywords: animal models,clinical cohorts,development,epigenetics,fasd,fetal programming,prenatal alcohol exposure
                Data availability:
                Keywords: animal models, clinical cohorts, development, epigenetics, fasd, fetal programming, prenatal alcohol exposure

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