Systems-wide analysis of histone lysine 2-hydroxyisobutyrylation pathway

组蛋白赖氨酸 2-羟基异丁酰化途径的全系统分析

• 批准号: 9458207
• 负责人: YINGMING ZHAO
• 金额: $ 44.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-20 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9458207
• 关键词: Area; Binding; Binding Proteins; Biochemical; Biochemistry; Biological; Biological Assay; Biological Models; Biological Process; Biology; Cardiovascular Diseases; Cardiovascular system; Cell Cycle Stage; Cell Differentiation process; Cell Extracts; Cell physiology; Cells; ChIP-seq; Chromatin; Chromatin Structure; Coenzyme A; Data; Data Set; Development; Diabetes Mellitus; Disease; Drug Targeting; Enzymes; Epigenetic Process; Experimental Models; Fractionation; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genomics; Germ Cells; Histone Acetylation; Histones; Human; Immune System Diseases; In Vitro; Knowledge; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Meiosis; Methylation; Molecular; Mus; N-terminal; Pathway interactions; Peptide Library; Peptides; Positioning Attribute; Post-Translational Protein Processing; Process; Proteins; Proteomics; Reader; Recombinants; Regulatory Element; Reporting; Research; Role; Site; Spermatogenic Cell; System; Systems Biology; Testing; Tetrahymena; Tissues; Universities; Work; base; cell type; embryonic stem cell; epigenome; epigenomics; experimental study; histone methylation; histone modification; histone-binding proteins; human disease; improved; in vitro activity; in vivo; male; mouse genome; nerve stem cell; nervous system disorder; novel; protein complex; public health relevance; reconstitution; sperm cell; stem cell biology; stem cell differentiation; stoichiometry; success; thermophilic organism; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): Histone post-translational modification (PTM, or histone mark) is critical to dynamic modulation of chromatin structure and function. Dysregulation of histone modification processes contributes to the development of many diseases, such as cancer, cardiovascular and neurological diseases. We recently reported a new, evolutionarily-conserved histone mark, lysine 2-hydroxyisobutyrylation (Khib). We showed that Khib is present among 63 histone lysine residues in both human and mouse, more than the known numbers of the widely studied histone acetylation (Kac) and methylation (Kme) sites. We also obtained multiple lines of evidence that suggest important and unique biological functions of histone Khib: this class of histone modification shows distinct genomic distributions from the widely studied histone Kac during male germ cell differentiation; it is associated with active gene transcription and H4K8hib is a better indicator for high gene expression than its corresponding H4K8ac; histone Khib can direct in vitro transcription in a manner dependent on 2-hydroxyisobutyryl CoA, suggesting that histone Khib impacts chromatin structure and transcriptional activity; histone Khib has different profiles between transcriptionally active and transcriptionally silent chromatin in Tetrahymena thermophile, in different cell cycle stages, and during mouse spermotogenesis. These results suggest that histone Khib is structurally and mechanistically different from histone Kac. The major players regulating histone Khib pathway would break new ground in epigenetic research and improve our understanding of cellular physiology and human disease. In the proposed research, we will study histone Khib pathway using an integrated approach. We will identify histone Khib-regulatory enzymes and direct binding proteins of histone Khib marks. We will also investigate genomic distributions of key histone Khib marks in mouse genome, and compare these data with those of the well-studied histone acetylation and methylation marks. Our team is well positioned to carry out this project, because of our extensive expertise in the areas of epigenomics, biochemistry, proteomics, stem cell biology, and the tremendous preliminary results we generated. This study will overcome a major hurdle to study biology of histone Khib pathway by revealing key regulatory elements and likely characterize novel epigenetic mechanisms, perhaps analogous to the characterization of histone Kac and Kme pathways.

 描述（由申请人提供）：组蛋白翻译后修饰（PTM，或组蛋白标记）对染色质结构和功能的动态调节至关重要。组蛋白修饰过程的失调有助于许多疾病的发展，例如癌症、心血管和神经系统疾病。我们最近报道了一个新的，进化上保守的组蛋白标记，赖氨酸2-羟基异丁酰化（Khib）。我们发现，Khib存在于人类和小鼠的63个组蛋白赖氨酸残基中，超过了广泛研究的组蛋白乙酰化（Kac）和甲基化（Kme）位点的已知数量。我们还获得了多条证据，表明组蛋白Khib的重要和独特的生物学功能：这类组蛋白修饰在雄性生殖细胞分化过程中显示出与广泛研究的组蛋白Kac不同的基因组分布;它与活性基因Kac的表达相关。 转录，H4 K8 hib比其相应的H4 K8 ac是更好的基因高表达指标;组蛋白Khib可以以依赖于2-羟基异丁酰CoA的方式指导体外转录，表明组蛋白Khib影响染色质结构和转录活性;在嗜热四膜虫不同的细胞周期阶段，和小鼠精子发生过程中的作用。这些结果表明组蛋白Khib在结构和机制上不同于组蛋白Kac。调控组蛋白Khib通路的主要参与者将在表观遗传学研究中开辟新天地，并提高我们对细胞生理学和人类疾病的理解。在本研究中，我们将采用综合方法研究组蛋白Khib通路。我们将确定组蛋白Khib调控酶和组蛋白Khib标记的直接结合蛋白。我们还将研究小鼠基因组中关键组蛋白Khib标记的基因组分布，并将这些数据与研究充分的组蛋白乙酰化和甲基化标记的数据进行比较。由于我们在表观基因组学、生物化学、蛋白质组学、干细胞生物学领域的广泛专业知识以及我们产生的巨大初步结果，我们的团队完全有能力开展这一项目。这项研究将克服一个主要的障碍，研究组蛋白Khib通路的生物学通过揭示关键的调控元件，并可能表征新的表观遗传机制，也许类似于组蛋白Kac和Kme通路的表征。