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

• 批准号: 10401790
• 负责人: PENG JIN
• 金额: $ 104.08万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10401790
• 关键词: ASD patient; 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; 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; RNA metabolism; 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neurogenesis; neuropsychiatric disorder; social relationships; transcriptome; transcriptome sequencing; unpublished works

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 Among different RNA modifications, our published and unpublished works suggest that m6A, m3C and m1A are dynamic and could play important roles during neurodevelopment and, potentially, contribute to developmental pathology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.

项目概要 表观遗传调控已被证明在神经发育和神经精神病学中发挥着关键作用 失调。除了 DNA 和组蛋白修饰外，还有 150 多种转录后修饰 核糖核苷已在多种类型的RNA中被鉴定。此外，最近的研究表明 转录后信使 RNA (mRNA) 修饰是动态调节的并显着影响 基因表达的结果。这些动态 RNA 修饰代表了基因的一个重要新领域 以“RNA表观遗传学”或“表观转录组学”的形式进行表达调控。不同RNA之间 修改后，我们已发表和未发表的作品表明 m6A、m3C 和 m1A 是动态的，可以 在神经发育过程中发挥重要作用，并且如果出现以下情况，可能会导致发育病理学： 失调。自闭症谱系障碍 (ASD) 是一组临床上异质性的发育障碍 通常的特点是社会关系受损、语言和沟通受损、能力有限 兴趣范围和刻板行为。我们发现 ASD 相关基因受到广泛影响 人类大脑发育过程中的RNA修饰。我们进一步开发了强大的技术和 在转录组范围内“定量”分析/映射这些 RNA 特异性修饰的管道 人类。在这项拟议的 PsychENCODE 研究中，我们将使用死后组织和人类诱导多能 干细胞衍生的类器官可系统地绘制三种不同的 mRNA/lncRNA 修饰（m6A、m3C 和 m1A）在正常人脑发育过程中并识别未受影响的捐赠者之间的任何差异模式 和自闭症谱系障碍（ASD）患者。这些数据集将提供 RNA 标记如何影响全球的蓝图 转录组，我们将注释对大脑发育重要的关键转录本的显着修改 和功能。我们提出的工作将识别和功能注释对后转录至关重要的表观转录组标记。 人类大脑发育和成年期的转录基因表达调控。一个系统的 在人脑发育和 ASD 背景下分析这些 RNA 修饰可以提供新的 对神经发育失调的脆弱性关键节点的功能洞察。

项目成果

FMRP phosphorylation modulates neuronal translation through YTHDF1.

FMRP 磷酸化通过 YTHDF1 调节神经元翻译。

• DOI: 10.1016/j.molcel.2023.10.028
• 发表时间: 2023
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Zou,Zhongyu;Wei,Jiangbo;Chen,Yantao;Kang,Yunhee;Shi,Hailing;Yang,Fan;Shi,Zhuoyue;Chen,Shijie;Zhou,Ying;Sepich-Poore,Caraline;Zhuang,Xiaoxi;Zhou,Xiaoming;Jiang,Hualiang;Wen,Zhexing;Jin,Peng;Luo,Cheng;He,Chuan
• 通讯作者: He,Chuan

N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease.

• DOI: 10.1186/s13059-020-02249-z
• 发表时间: 2021-01-05
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Shafik AM;Zhang F;Guo Z;Dai Q;Pajdzik K;Li Y;Kang Y;Yao B;Wu H;He C;Allen EG;Duan R;Jin P
• 通讯作者: Jin P

Epitranscriptomic dynamics in brain development and disease.

• DOI: 10.1038/s41380-022-01570-2
• 发表时间: 2022-09
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Shafik, Andrew M.;Allen, Emily G.;Jin, Peng
• 通讯作者: Jin, Peng