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）对于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会导致许多疾病的发生，例如癌症、心血管和神经系统疾病。我们最近报道了一种新的、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 存在于人和小鼠的 63 个组蛋白赖氨酸残基中，比广泛研究的组蛋白乙酰化 (Kac) 和甲基化 (Kme) 位点的已知数量还要多。我们还获得了多项证据，表明组蛋白 Khib 具有重要且独特的生物学功能：此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；它与活性基因有关 转录和 H4K8hib 是比其相应的 H4K8ac 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；在嗜热四膜虫中，在不同的细胞周期阶段和小鼠精子发生过程中，组蛋白 Khib 在转录活性和转录沉默染色质之间具有不同的特征。这些结果表明组蛋白 Khib 在结构和机制上与组蛋白 Kac 不同。调节组蛋白 Khib 通路的主要参与者将为表观遗传学研究开辟新天地，并提高我们对细胞生理学和人类疾病的理解。在拟议的研究中，我们将使用综合方法研究组蛋白 Khib 通路。我们将鉴定组蛋白 Khib 调节酶和组蛋白 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，并将这些数据与经过充分研究的组蛋白乙酰化和甲基化标记的数据进行比较。我们的团队有能力开展这个项目，因为我们在表观基因组学、生物化学、蛋白质组学、干细胞生物学领域拥有丰富的专业知识，并且我们取得了巨大的初步成果。这项研究将通过揭示关键调控元件并可能表征新的表观遗传机制（可能类似于组蛋白 Kac 和 Kme 途径的表征）来克服组蛋白 Khib 途径生物学研究的主要障碍。