Control of gene expression in neural stem cells by crosstalk between messenger RNA methylation and histone modification

通过信使RNA甲基化和组蛋白修饰之间的串扰控制神经干细胞中的基因表达

• 批准号: 10408701
• 负责人: Anindya Bagchi
• 金额: $ 39万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408701
• 关键词: Acetylation; Acetyltransferase; Adenosine; Binding; Biochemical; Biological Models; Biological Process; Brain; Cells; Central Nervous System Diseases; Chromatin; Complex; Defect; Development; EP300 gene; EZH2 gene; Embryo; Enzymes; Essential Genes; Fibroblasts; Future; Gene Expression; Genes; Genetic Transcription; Genetic study; Histone Acetylation; Histone H3; Histones; Human; In Vitro; Investigation; Knock-out; Knockout Mice; Link; Lysine; Mammalian Cell; Messenger RNA; Methylation; Methyltransferase; Modification; Molecular; Mus; Mutation Analysis; Neuronal Differentiation; Neurons; Phenotype; Play; Positioning Attribute; RNA; RNA Probes; RNA Stability; RNA methylation; Regenerative Medicine; Regulation; Regulator Genes; Reporting; Research; Role; Site; Site-Directed Mutagenesis; Source; Supporting Cell; Testing; Tissues; Transcript; Validation; Work; base; conditional knockout; epitranscriptomics; gene function; gene regulatory network; gene repression; genome-wide; genomic locus; histone modification; human disease; in vivo; malignant neurologic neoplasms; mouse genetics; neocortical; nerve stem cell; nervous system disorder; neurogenesis; neuroregulation; novel; self-renewal; stem cell differentiation; stem cell genes; stem cell proliferation; success; transcriptome; transcriptomics; transplant model; trend

PROJECT SUMMARY Emerging evidence suggests that the post-transcriptional messenger RNA (mRNA) modification N6- methyladenosine (m6A) is a fundamental mRNA regulatory mechanism. This modification tags thousands of mRNAs and regulates their activities through diverse mechanisms. Phenotypes seen following knockout of m6A methyltransferases in mouse or human neural stem cells (NSCs) support the idea that the modification is required for proper NSC activity and for brain development. We recently discovered crosstalk between m6A and histone post-transcriptional modifications (PTMs) in NSCs. Specifically, we reported a dual function of m6A in regulating both active and repressive histone PTMs, and showed that these histone PTMs target different functional classes of NSC genes to keep NSCs at ground state. In this application, we continue to use NSCs as a model system in order to investigate molecular mechanisms underlying m6A regulation of histone PTMs. We will ask whether m6A modulates expression of histone-modifying enzymes (Aim 1), or regulates binding of histone-modifying enzymes to RNA and/or chromatin (Aim 2). This work will guide future investigation of interactions between RNA- and histone- modifications. In addition, since m6A mRNA modification represents a fundamental gene regulatory mechanism in development and is perturbed in some human neurological diseases and cancers, mechanistic analysis of m6A function could significantly advance our understanding of normal development and provide a basis for future investigation of m6A dysregulation in human diseases.

项目摘要 新兴证据表明，转录后信使RNA（mRNA）修饰N6- 甲基腺苷（M6A）是一种基本的mRNA调节机制。此修改标记数千个 mRNA并通过各种机制来调节其活动。敲除之后看到的表型 小鼠或人神经干细胞（NSC）中的M6a甲基转移酶支持修饰是 适当的NSC活动和大脑发育所必需的。 我们最近在转录后修改（PTMS）之间发现了M6A和组蛋白之间的串扰 NSC。具体而言，我们报道了M6A在调节活性和抑制性组蛋白PTM中的双重函数， 并表明这些组蛋白PTM靶向不同的NSC基因的功能类别，以使NSC保持在地面 状态。在此应用中，我们继续使用NSC作为模型系统，以研究分子 组蛋白PTM的M6A调节的机制。我们将询问M6A是否调节 组蛋白改性酶（AIM 1），或调节组蛋白改性酶与RNA和/或的结合 染色质（AIM 2）。 这项工作将指导对RNA和组蛋白修饰之间相互作用的未来研究。在 此外，由于M6A mRNA修饰代表了发展中的基因调节机制 并且在某些人类神经系统疾病和癌症中受到干扰，M6A功能的机械分析 可以大大提高我们对正常发展的理解，并为未来提供基础 人类疾病中M6A失调的研究。