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.

项目总结/文摘

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