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Histone lactylation pathway in hair cycle: deacylases and their protein targets

毛发周期中的组蛋白乳酰化途径：脱酰酶及其蛋白质靶标

基本信息

批准号：
10412929
负责人：
Hening Lin
金额：
$ 67.55万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412929
关键词：
Acetylation Acetyltransferase Area Behavior Biochemical Biochemistry Bioinformatics Biology Cell physiology Cells Chemicals Chemistry Chromatin Coenzyme A Cultured Cells DNA Data Data Set Deacetylase Diabetes Mellitus Disease EP300 gene Energy Metabolism Environment Enzymatic Biochemistry Enzymes Epigenetic Process Foundations Gene Expression Regulation Genes Goals Growth Hair Hair follicle structure Histone Deacetylase Histones Human Hypoxia Immune response Infrastructure Knock-out Knowledge Laboratories Lysine Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolism Methylation Modification Molecular Mus Pathologic Pathway interactions Periodicity Phase Physiological Physiology Play Positioning Attribute Post-Translational Protein Processing Proteins Proteomics Reaction Regulatory Element Regulatory Pathway Research Role Site Skin Substrate Specificity System Testing Tissues Transcriptional Regulation Warburg Effect Western Blotting adult stem cell base chromatin immunoprecipitation deep sequencing epigenetic regulation experimental study insight knock-down overexpression programs response stem cell differentiation stem cells transcriptome sequencing

项目摘要

Emerging lines of evidence suggest an intimate crosstalk among energy metabolism, metabolites and epigenetics. Post-translational modifications (PTMs) on histones (histone “marks”) (e.g., lysine acetylation (Kac) and methylation (Kme)) are known to be regulated by metabolism, contributing to the epigenetic programs that are associated with cellular physiology and disease. However, we do not yet know if additional histone PTM pathways exist and if they can be modulated by diverse cellular metabolites. Thus, chemistry and biochemistry of metabolites-mediated chromatin changes remain poorly characterized. Lactate, a widely known cellular metabolite, can be dramatically induced under some cellular conditions (e.g. hypoxia) and in the Warburg effect, an observation most commonly shared among diverse cancers and associated with many diseases. Lactate concentration can rise to 20-40 mM in cancer tissues. Although this compound was discovered ~200 years ago, its non-metabolic functions in physiology (e.g., hypoxia, stem cell differentiation and immunoresponse) and disease (e.g., cancer and diabetes) remain unknown, representing a long-standing question in biology. We recently discovered a lactate-derived, new lysine modification, lysine lactylation (Kla). We comprehensively validated this PTM by chemical and biochemical approaches. This PTM can be stimulated by the Warburg effect-derived lactate and has different temporal dynamics from the widely studied lysine acetylation (Kac). Our epigenetic studies suggest that histone Kla represents a new type of metabolism- regulated epigenetic changes and contributes to gene regulation. We hypothesize that the histone Kla pathway is molecularly distinct from Kac pathway and contribute to gene regulation. We therefore propose to characterize the Kla pathway by defining its key regulatory elements: enzymes that can remove the modification (or delactylases), and their targets on histones and non-histone substrate proteins. We will also study their role in epigenetic regulation in cyclic behavior of hair follicle stem cells (HFSCs) in which lactate and its regulatory enzyme play a key role. We will use an integrated strategy involving chemical biology, enzymology, quantitative proteomics, and biochemistry approaches. The knowledge gained from this study will likely have a broad impact on our understanding of epigenetics, and will lay a foundation for studying Kla and the Warburg effect.

越来越多的证据表明，能量代谢、代谢物和代谢之间存在密切的相互作用