How might epigenetic dysregulation in early embryonic life contribute to autism spectrum disorder?

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Date: Feb. 2015
From: Epigenomics(Vol. 7, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Editorial
Length: 2,354 words
Lexile Measure: 1800L

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Author(s): Esther R Berko aff1 aff2 , John M Greally aff1

Keywords:

autism; DNA methylation; embryo; epigenetic

The potential for nongenetic susceptibility to mediate part of the risk of autism spectrum disorder (ASD) has prompted a number of studies to date, all showing evidence for epigenetic differences characterizing the individuals with ASD. The modest differences in DNA methylation observed have indicated an underlying cellular mosaicism for epigenetic dysregulation. The studies to date have not comprehensively addressed potential confounding issues like cell subcomposition differences, transcriptional and DNA sequence variability. Additionally, it is possible that mutations in protein-coding genes encoding transcriptional and chromatin regulatory proteins lead to the epigenetic changes in a subset of individuals with ASD. More definitive studies are now needed to allow higher confidence insights into epigenetic events occurring in early embryogenesis in individuals with ASD.

Not all problems with genes have to do with their DNA sequence. If a gene with a completely normal DNA sequence capable of encoding a functional protein cannot be switched on appropriately, the effect for the cell is likely to be the same as a loss of function mutation of that gene. Problems of this type that remain heritable through cell divisions have been attributed to the subset of transcriptional regulatory mechanisms that are described as 'epigenetic.' DNA methylation has transcriptional regulatory properties and biochemical properties that are genuinely epigenetic [1 ], whereas other transcriptional regulatory mechanisms have not been proven to have the same heritability at the molecular level, although there is some evidence for heritability mechanisms of some histone post-translational modifications [2 ]. Genome-wide studies of these potentially epigenetic regulatory processes define the 'epigenome,' and represent a first means of seeking a role for abnormal regulation of transcription in phenotypic and disease studies.

The potential role for epigenetic dysregulation contributing to the pathogenesis of autism spectrum disorder (ASD) is a current major focus of interest. This interest is in part driven by the desire to understand why an individual developed ASD in the first place, and in part by the recognition that the inherently malleable epigenome may be a target for intervention to reverse any deleterious molecular events, potentially allowing amelioration of the ASD phenotype. Furthermore, as we try to understand how the broad and vague category of 'environmental' agents influence the risk of susceptibility to ASD [3 ], the epigenome is an attractive candidate for study as a potential mediator of these influences.

There have now been several studies of epigenetic dysregulation in ASD. An early study looked at trimethylation of the lysine at position 4 of the histone H3 protein (H3K4me3) in neuronal nuclei isolated from prefrontal cortex from post mortem brains of 16 subjects with ASD and 16 controls. Sequencing of the DNA enriched by chromatin immunoprecipitation (ChIP-seq) showed a broadening of the H3K4me3 peaks at gene promoters in some of the ASD subjects, providing a suggestion that there could be abnormal regulation of transcription in brains of individuals with ASD [4 ]. DNA methylation studies of peripheral blood...

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Gale Document Number: GALE|A409374831