Epigenomic Dysregulation of Neurodevelopmental Genes Underlies Autism Spectrum Disorders

项目概要/摘要 自闭症谱系障碍（ASD）包括一组复杂和异质的 神经发育性疾病，包括社会，行为和语言等共同特征的严重程度 损伤越来越多的证据表明，只有不到10%的ASD患者携带罕见的结构DNA， 变异和突变具有很强的重复性，这表明环境和表观遗传因素 在大多数情况下，通过破坏大脑发育过程中的关键神经原性过程来促成。事实上，Prior 研究已经观察到ASD患者在早期生命中不寻常的大脑生长，这种表型补充了 神经发生、迁移、突触发生和增殖缺陷的神经病理学证据。正常 神经发育需要基因表达/前mRNA剪接的协调时空调节， 表观遗传修饰，特别是涉及神经发生、迁移和神经元功能的基因。一个 大脑的重要区域富含有助于神经发生、生长和发育的神经祖细胞， hodology是侧脑室的脑室下区（SVZ）。在检查这个神经原区域， 自闭症患者和正常发育个体之间的表观遗传变化，我们的初步数据表明， 异常的DNA甲基化（一种表观遗传学机制）发生在先前基因的可变剪接外显子上， 与自闭症有关的DNA序列突变，MeCP 2，与基因的剪接缺陷有关， ASD个体没有这样的突变。DNA甲基化和其他染色质修饰的改变 ASD似乎很普遍。总之，这些结果暗示SVZ的表观遗传失调， 导致ASD的神经病理学和异质表型表达。但 表观遗传失调可能导致ASD的后果和程度在很大程度上仍然是 未开发的我们试图填补这一重要的知识空白。根据我们的初步数据，我们 假设染色质景观的改变，特别是基因内DNA甲基化状态， 神经发育基因通过异常前mRNA剪接事件促进转录组学变化 潜在的ASD为了证实这一假设，我们将利用我们独特的尸检样本 来自特发性自闭症诊断和年龄匹配的典型发育男性的SVZ组织，旨在 确定（1）表观基因组（即全基因组DNA甲基化和组蛋白 修饰状态）和（2）ASD中的RNA转录组。整合这些数据集将提供新的见解 神经发育基因可能在ASD中失调的机制，并可能揭示 这些疾病的有用的治疗靶点。此外，本研究还可能拓宽ASD研究的领域 阐明表观遗传病因，这也可能捕获和解释以前未探索的 环境危险因素和ASD的异质性表型表达。

PROJECT SUMMARY/ABSTRACT Autism spectrum disorders (ASD) comprises a group of complex and heterogeneous neurodevelopmental diseases that range in severity of shared traits including social, behavioral, and language impairments. Mounting evidence indicate that fewer than 10% of patients with ASD harbor rare structural DNA variations and mutations with strong penetrance, suggesting that environmental and epigenetic factors contribute to most cases by disrupting critical neurogenic processes during brain development. Indeed, prior studies have observed unusual brain growth in early life of patients with ASD, a phenotype that complements neuropathological evidence of defects in neurogenesis, migration, synaptogenesis, and proliferation. Normal neurodevelopment entails coordinated spatiotemporal regulation of gene expression/pre-mRNA splicing and epigenetic modifications, particularly of genes involved in neurogenesis, migration, and neuronal function. An important region of the brain enriched for neural progenitors that contribute to neurogenesis, growth, and hodology is the subventricular zone (SVZ) of the lateral ventricle. On examining this neurogenic region for epigenetic changes between autistic and typically developing individuals, our preliminary data indicated that aberrant DNA methylation (an epigenetic mechanism) at an alternatively spliced exon of a gene previously implicated in autism by DNA sequence mutations, MeCP2, associates with splicing defects of the gene in an ASD individual without such mutations. Alterations to DNA methylation and other chromatin modifications in ASD appear to be widespread. Together, these results implicate epigenetic dysregulation of the SVZ in contributing to the neuropathological and heterogeneous phenotypic expression of ASD. However, the consequence of and extent to which epigenetic dysregulation may contribute to ASD remain largely unexplored. We seek to fill this very important gap in knowledge. Based on our promising preliminary data, we hypothesize that alterations to the chromatin landscape, in particular intragenic DNA methylation states, over neurodevelopmental genes contribute to transcriptomic changes via aberrant pre-mRNA splicing events underlying ASD. To address this hypothesis, we will take advantage of our unique collection of postmortem SVZ tissue from idiopathic autism-diagnosed and age-matched typically developing males, and aim to determine the extent of alterations to (1) the epigenome (i.e. genome-wide DNA methylation and histone modification states) and (2) the RNA transcriptome in ASD. Integrating these datasets will provide novel insight into the mechanism(s) by which neurodevelopmental genes may be dysregulated in ASD and reveal potentially useful therapeutic targets for the disorders. Additionally, this study will likely broaden the field of ASD research to elucidate an epigenetic etiology, which may also capture and account for previously unexplored environmental risk factors and the heterogeneous phenotypic expression of ASD.