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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

基本信息

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
项目类别：
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

项目摘要

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.