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Dynamic RNA Modifications in human brain development and autism

人类大脑发育和自闭症中的动态RNA修饰

基本信息

批准号：
9751395
负责人：
PENG JIN
金额：
$ 95.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751395
关键词：
Adult Affect Autopsy Behavior Brain CRISPR/Cas technology Cell Nucleus Chromosomal Rearrangement Clinical Communication DNA Modification Process Data Data Set Defect Development Disease Elements Epigenetic Process FMR1 Fragile X Syndrome Gene Expression Gene Expression Profile Gene Expression Regulation Gene Mutation Genes Genetic Transcription Human Impairment Lead Link Maps Messenger RNA Metabolism Modeling Modification Mus Mutation Neurodevelopmental Disorder Neurons Organoids Outcome Pathology Patients Pattern Play Prefrontal Cortex Production Prosencephalon Proteins Protocols documentation Publishing Quantitative Trait Loci RNA RNA Splicing RNA analysis Reader Ribonucleosides Role Schizophrenia Second Pregnancy Trimester Small Nuclear RNA Spatial Distribution Structure Technology Tissues Transcript Translations Variant Work autism spectrum disorder autistic brain tissue cell type developmental disease epigenetic regulation epitranscriptome epitranscriptomics fetal histone modification human tissue in vivo induced pluripotent stem cell insight interest language impairment neurodevelopment neurogenesis neuropsychiatric disorder social transcriptome transcriptome sequencing unpublished works

项目摘要

PROJECT SUMMARY Epigenetic regulation has been shown to play pivotal roles in neurodevelopmental and neuropsychiatric disorders. In addition to DNA and histone modifications, more than 150 post-transcriptionally modified ribonucleosides have been identified in various types of RNA. Furthermore, recent studies have suggested that post-transcriptional messenger RNA (mRNA) modifications are dynamically regulated and significantly impact the outcomes of gene expression. These dynamic RNA modifications represent a critical new realm for gene expression regulation in the form of “RNA epigenetics” or “Epitranscriptomics”. Among different RNA modifications, our published and unpublished works suggest that m6A, m3C and m1A are dynamic and could play important roles during neurodevelopment and, potentially, contribute to developmental pathology if dysregulated. Autism spectrum disorder (ASD) is a clinically heterogeneous group of developmental disorders frequently characterized by impaired social relationships, impaired language and communication, a limited range of interests and stereotypic behaviors. We have found that ASD-linked genes are subject to extensive RNA modifications during human brain development. We have further developed robust technologies and pipelines to “quantitatively” profile/map these RNA specific modifications at the transcriptome-wide level in humans. In this proposed PsychENCODE study, we will use postmortem tissue and human induced pluripotent stem cell-derived organoids to systematically map three distinct mRNA/lncRNA modifications (m6A, m3C and m1A) during normal human brain development and identify any differential patterns between unaffected donors and patients with ASD. These datasets will provide a blueprint of how RNA marks impact the global transcriptome and we will annotate prominent modifications on key transcripts important for brain development and function. Our proposed work will identify and functionally annotate epitranscriptome marks critical to post- transcriptional gene expression regulation across human brain development and adulthood. A systematic analysis of these RNA modifications in the context of human brain development and ASD could provide new functional insights into critical nodes of vulnerability for dysregulated neural development.

项目总结