Epigenomic Dysregulation of Neurodevelopmental Genes Underlies Autism Spectrum Disorders

项目摘要/摘要 自闭症谱系障碍(ASD)由一组复杂的、异质性的 包括社会、行为和语言在内的共同特征的严重程度不等的神经发育疾病 减损。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 具有很强外显性的变异和突变，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发生过程而起作用。的确，普赖斯 研究已经观察到ASD患者早期脑发育异常，这是一种补充了 神经发生、迁移、突触形成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和 表观遗传修饰，尤指涉及神经发生、迁移和神经功能的基因。一个 大脑中丰富的神经前体的重要区域，有助于神经发生、生长和 血液学是指侧脑室的室下区(SVZ)。关于检查这一神经源性区域 自闭症患者和典型发育个体之间的表观遗传学变化，我们的初步数据表明 先前基因外显子选择性剪接的异常DNA甲基化(一种表观遗传学机制) 与DNA序列突变有关的自闭症，MeCP2与基因剪接缺陷有关 无此突变的ASD个体。DNA甲基化和其他染色质修饰的改变 ASD似乎很普遍。综上所述，这些结果暗示SVZ的表观遗传失调。 在ASD的神经病理和异质性表型表达中起重要作用。然而， 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存在 未被开发的。我们寻求填补这一非常重要的知识空白。基于我们充满希望的初步数据，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的前mRNA剪接事件参与转录变化 潜在的ASD。为了解决这一假设，我们将利用我们独特的尸检资料 来自特发性自闭症的SVZ组织-诊断为典型的发育期男性，年龄匹配，目的是 确定(1)表观基因组(即全基因组DNA甲基化和组蛋白)的改变程度 修饰状态)和(2)ASD中的RNA转录组。集成这些数据集将提供新的见解 神经发育基因可能在自闭症中失调的机制(S)并揭示 这些疾病的有效治疗靶点。此外，这项研究可能会拓宽自闭症的研究领域。 为了阐明表观遗传学病因学，这也可能捕捉和解释以前未探索过的 环境风险因素与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.