Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder

Abstract

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear.The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested an homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD.The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

Development and the epigenome: the ‘synapse’ of gene–environment interplay

“…Further, Qureshi and Mehler (Qureshi & Mehler, ) and Hodes (Hodes, ) have reviewed evidence that DNA methylation, histone modifications and ncRNAs may all be implicated in the known sexual dimorphisms arising during brain development, which may underlie differential susceptibility among males and females to various forms of psychopathology. Epigenetic links to neurodevelopmental abnormalities and disorders of mental health include the distinctive methylation patterns found within hundreds of gene loci, among patients with autism spectrum disorder and other neurodevelopmental syndromes (Shulha, Cheung, Whittle, Wang, Virgil et al ., ; Berko, Suzuki, Beren, Lemetre, Alaimo et al ., ). Children with Down Syndrome, with their triplication of chromosome 21, should theoretically have 50% more expression of those chromosomal genes, but their actual transcription varies from that expectation, suggesting that DNA methylation, histone modification and possibly other epigenetic events may be involved (Dekker, De Deyn & Rots, ).…”

Methylomic analysis of salivary DNA in childhood ADHD identifies altered DNA methylation in VIPR2

“…Although the degree of cross‐tissue concordance in DNA methylation remains in question, these studies still hold potential for novel discovery of liability markers or identify targets for future investigation in neural systems (Aberg et al., ; Horvath, ). Recent studies of peripheral tissue DNA methylation have identified epigenetic variation associated with autism (Berko et al., ; Wong et al., ) and psychosis (Aberg et al., ; Dempster et al., ), with promising results. In ADHD, a small number of prior studies have examined DNA methylation in candidate genes (van Mil et al., ; Xu et al., ) with encouraging results.…”

Microbiome Disturbances and Autism Spectrum Disorders

“…The term epigenetics has become vastly overused to define broadly any transcriptomic change occurring independent of DNA mutation. The field of neuroepigenetics was born under these auspices and is currently invoked as the genesis of many neurologic disorders not explained by genetics alone, including ASD (Wilkinson and Campbell, 2013;Berko et al, 2014;Ladd-Acosta et al, 2014;Lesseur et al, 2014;Tordjman et al, 2014;Wong et al, 2014). Alterations in the gut microbiome might trigger epigenetic changes leading to downstream behavioral manifestations (Mischke and Plösch, 2013;Kumar et al, 2014;Stilling et al, 2014).…”