Systematic screening for new histone marks and studying their epigenetic function

系统筛选新组蛋白标记并研究其表观遗传功能

• 批准号: 10579280
• 负责人: YINGMING ZHAO
• 金额: $ 50.89万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579280
• 关键词: Acylation; Area; Biochemical; Biological; Biological Process; Biology; Cells; Cellular Metabolic Process; ChIP-seq; Chemical Structure; Chemicals; Chromatin; Chromatin Structure; DNA; Data; Disease; Elements; Epigenetic Process; Fractionation; Gene Expression; Generations; Genetic Transcription; Genome; Goals; High Pressure Liquid Chromatography; Histones; Hypoxia; Laboratories; Link; Lipids; Lysine; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Metabolic Diseases; Metabolism; Methods; Modification; Nature; Output; Pathologic; Pathway interactions; Peptides; Physiological; Play; Positioning Attribute; Post-Translational Protein Processing; Productivity; Proteomics; Publications; Pyruvate; Regulation; Research; Role; Spermatogenesis; Structure; Technology; Transcriptional Regulation; Warburg Effect; bioinformatics tool; cell growth regulation; chromatin immunoprecipitation; epigenetic regulation; epigenomics; experimental study; interest; novel; programs; screening; skills

Epigenetic regulation is critical to diverse biological processes and diseases. Post-translational modifications (PTMs) in histones are generally considered to be a major group of epigenetic marks, contributing to the epigenetic program that dictates diverse DNA-templated biological outputs. Our team has recently identified nine types of novel histone PTMs (lysine propionylation, lysine butyrylation, lysine malonylation, lysine succinylation, lysine glutarylation, lysine crotonylation, lysine 2-hydroxyisobutyrylation, lysine 3-hydroxybutyrylation, and lysine benzoylation). Importantly, we and others demonstrated critical roles for these new PTM pathways by revealing their unique functions in the transcriptional control of gene expression and cellular regulation, and by linking them to multiple inborn metabolic diseases. Some of these histone marks can be stimulated by cellular levels of their corresponding short-chain lipids, thus suggesting new mechanisms for metabolism-regulated epigenetic changes. This application is based on the tremendous expertise we gained during our earlier studies on identification and characterization of nine novel types of histone marks. We hypothesize that additional, undescribed types of histone PTMs are present in mammalian histones. Our hypothesis is supported by our preliminary data identifying multiple undescribed PTMs in histones, the chemical structures of which are either undefined or remain to be fully validated. We propose to use an integrated approach, employing technologies that have been well established and fully validated in the laboratories of our team, to comprehensively screen for novel types of histone PTMs. Our team is best positioned to find these histone marks because of the tremendous skills and numerous technologies we have accumulated, and the high productivity we have demonstrated in our recent identification of the novel types of histone marks. We will first comprehensively screen for new types of histone marks and validate them by both chemical and biochemical methods. We will then investigate their epigenetic roles during spermatogenesis. New types of histone marks will significantly advance our understanding of chromatin structure and function, might open unforeseen avenues for epigenetic studies, and may even shift the focus of current research on epigenetic mechanisms and disease.

表观遗传调控对于多种生物过程和疾病至关重要。翻译后 组蛋白修饰（PTM）通常被认为是表观遗传标记的主要组， 为表观遗传程序做出贡献，该程序决定不同的 DNA 模板生物输出。我们的团队有 最近发现了九种新型组蛋白 PTM（赖氨酸丙酰化、赖氨酸丁酰化、赖氨酸 丙二酰化、赖氨酸琥珀酰化、赖氨酸戊二酰化、赖氨酸巴豆酰化、赖氨酸2-羟基异丁酰化、 赖氨酸3-羟基丁酰化和赖氨酸苯甲酰化）。重要的是，我们和其他人发挥了关键作用 通过揭示这些新的 PTM 途径在基因转录控制中的独特功能 表达和细胞调节，并将它们与多种先天代谢疾病联系起来。其中一些 组蛋白标记可以通过其相应的短链脂质的细胞水平来刺激，因此表明 代谢调节表观遗传变化的新机制。该应用程序基于巨大的 我们在早期研究中获得了九种新类型的鉴定和表征的专业知识 组蛋白标记。我们假设哺乳动物中存在其他未描述类型的组蛋白 PTM 组蛋白。我们的假设得到了我们的初步数据的支持，该数据识别了多个未描述的 PTM 组蛋白，其化学结构要么未定义，要么有待充分验证。我们建议 采用综合方法，采用在该领域已成熟且经过充分验证的技术 我们团队的实验室，全面筛选新型组蛋白翻译后修饰。我们的团队是最好的 由于我们拥有丰富的技能和众多的技术，我们有能力找到这些组蛋白标记 积累，以及我们在最近识别新型类型中所展示的高生产力 组蛋白标记。我们将首先全面筛选新型组蛋白标记，并通过两者进行验证 化学和生化方法。然后我们将研究它们在精子发生过程中的表观遗传作用。 新型组蛋白标记将显着增进我们对染色质结构和功能的理解， 可能会为表观遗传学研究开辟不可预见的途径，甚至可能将当前研究的重点转移到 表观遗传机制和疾病。