Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
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DOI：
10.1371/journal.pgen.1004402
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发表时间：
2014-05-01
期刊：
影响因子：
4.5
通讯作者：
Greally, John M.
中科院分区：
文献类型：
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作者：
Berko, Esther R.;Suzuki, Masako;Greally, John M.
DNA突变事件在自闭症谱系障碍（ASD）中越来越多地被发现，但表观基因组失调在该病发病机制中的潜在额外作用仍不清楚。表观基因组作为发育过程中环境影响的可能介导者是令人感兴趣的，其编码通过子代细胞的功能改变所反映的细胞记忆。高龄产妇（AMA）与患有ASD的孩子的风险增加有关，原因尚不清楚。为了探索AMA是否涉及隐性非整倍体或表观遗传失调导致后代ASD，我们使用定量全基因组DNA甲基化分析测试了47名ASD患者的同质外胚层细胞类型，并与48名>= 35岁母亲所生的典型发育（TD）对照进行了比较。我们发现，DNA甲基化模式失调，在这些人的外胚层细胞中，由于受试者的年龄，性别和祖先的单倍型的混杂效应。我们没有发现镶嵌非整倍性或拷贝数变异发生在这些受试者的差异甲基化区域。值得注意的是，在大脑中表达的基因中发现了具有独特DNA甲基化的基因座，并且编码的蛋白质产物显著富集，与已知的ASD引起基因产生的蛋白质产物相互作用，这代表了DNA突变机制损害的相同网络的表观基因组失调的扰动。结果表明在ASD受试者中存在表观遗传失调的外胚层衍生细胞的嵌合亚群。在这些由高龄母亲所生的ASD受试者中观察到的表观遗传失调可能与父母配子老化、胚胎发生期间的环境影响有关，或者可能是ASD中越来越多的染色质调节基因突变的结果。结果表明，表观遗传失调机制可能补充和相互作用的DNA突变的发病机制的障碍。
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 a 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.