Epigenomic Dysregulation of Neurodevelopmental Genes Underlies Autism Spectrum Disorders

神经发育基因的表观基因组失调是自闭症谱系障碍的基础

• 批准号: 9552273
• 负责人: Alika Keolaokalani Maunakea
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552273
• 关键词: Aberrant DNA Methylation; Address; Age; Aging; Alternative Splicing; Autistic Disorder; Autopsy; Biological Markers; Brain; Brain region; Cells; ChIP-seq; Chromatin; Collection; Communities; Complement; Complex; Coupled; DNA; DNA Methylation; DNA Sequence; Data; Data Set; Defect; Development; Diagnosis; Disease; Encephalitis; Environmental Risk Factor; Epigenetic Process; Etiology; Event; Exons; Gene Expression Regulation; Genes; Goals; Growth; Health; High-Throughput Nucleotide Sequencing; Histone Acetylation; Immune; Immunoprecipitation; Incidence; Individual; Knowledge; Life; Massive Parallel Sequencing; Messenger RNA; Methyl-CpG-Binding Protein 2; Modification; Molecular; Mutation; Neurons; Outcome; Patients; Pattern; Penetrance; Peripheral; Phenotype; Play; Process; RNA; RNA Splicing; Rare Diseases; Research; Resources; Role; Sampling; Severities; Specimen; Techniques; Technology; Tissues; Transcriptional Regulation; United States National Institutes of Health; Variant; autism spectrum disorder; base; behavioral impairment; brain tissue; chromatin immunoprecipitation; chromatin modification; cognitive function; epigenome; epigenomics; genome-wide; histone modification; innovation; insight; language impairment; lateral ventricle; mRNA Precursor; male; migration; nerve stem cell; neurodevelopment; neurogenesis; novel; potential biomarker; social; spatiotemporal; subventricular zone; synaptogenesis; therapeutic target; trait; transcriptome; transcriptome sequencing; transcriptomics

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.

项目摘要/摘要 自闭症谱系障碍（ASD）包括一组复杂而异质 神经发育疾病，包括社会，行为和语言在内的共同特征的严重性范围 障碍。越来越多的证据表明，仅不到10％的ASD港口稀有结构DNA患者 具有强大外观的变化和突变，表明环境和表观遗传因素 通过破坏大脑发育过程中关键的神经源过程来促进大多数情况。确实，先验 研究已经观察到ASD患者早期生命的异常大脑生长，这种表型补充 神经发生，迁移，突触发生和增殖中缺陷的神经病理学证据。普通的 神经发育需要协调基因表达/前mRNA剪接的时空调节 表观遗传修饰，特别是与神经发生，迁移和神经元功能有关的基因。一个 大脑的重要区域富含神经祖细胞，有助于神经发生，生长和 Hodology是侧心室的室室下区（SVZ）。在检查这个神经源区域 自闭症和通常发育中的个体之间的表观遗传变化，我们的初步数据表明 以前在基因的剪接外显子上异常的DNA甲基化（表观遗传机制） 由DNA序列突变（MECP2）与自闭症有关，与该基因的剪接缺陷有关 没有这种突变的ASD个体。对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 有助于ASD的神经病理学和异质表型表达。但是， 表观遗传失调可能导致ASD的后果和程度的程度很大 未探索。我们试图填补这一非常重要的知识差距。根据我们有希望的初步数据，我们 假设对染色质景观的改变，特别是基因内DNA甲基化状态 神经发育基因通过异常mRNA剪接事件有助于转录组变化 基础ASD。为了解决这一假设，我们将利用我们独特的验尸集合 从特发性自闭症诊断和年龄匹配的SVZ组织通常会发展为雄性，旨在 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 修改状态）和（2）ASD中的RNA转录组。集成这些数据集将提供新颖的见解 在ASD中神经发育基因可能失调的机制中，并可能揭示了潜在的 疾病的有用治疗靶标。此外，这项研究可能会扩大ASD研究领域 阐明表观遗传病因，该病因也可能捕获并说明了先前未探索的 环境风险因素和ASD的异质表型表达。

项目成果

Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study.

• DOI: 10.3389/fnins.2022.1023665
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Takahashi, Emi;Allan, Nina;Peres, Rafael;Ortug, Alpen;van der Kouwe, Andre J. W.;Valli, Briana A.;Ethier, Elizabeth;Levman, Jacob K.;Baumer, Nicole;Tsujimura, Keita;Vargas-Maya, Nauru Idalia;McCracken, Trevor;Lee, Rosa;Maunakea, Alika
• 通讯作者: Maunakea, Alika