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

• 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
• 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

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.

新出现的证据表明能量代谢、代谢物和代谢物之间存在密切的串扰。 表观遗传学。组蛋白的翻译后修饰 (PTM)（组蛋白“标记”）（例如赖氨酸乙酰化 （Kac）和甲基化（Kme））已知受代谢调节，有助于表观遗传 与细胞生理学和疾病相关的程序。然而，我们还不知道是否需要额外的 组蛋白 PTM 通路是否存在，以及它们是否可以通过多种细胞代谢物进行调节。因此，化学和 代谢物介导的染色质变化的生物化学仍然知之甚少。乳酸，一种广为人知的 细胞代谢物，在某些细胞条件下（例如缺氧）和在 瓦尔堡效应，一种在多种癌症中最常见的现象，并且与许多癌症相关 疾病。癌症组织中的乳酸浓度可升至 20-40 mM。虽然该化合物是 约 200 年前发现，其生理学中的非代谢功能（例如缺氧、干细胞分化） 和免疫反应）和疾病（例如癌症和糖尿病）仍然未知，代表着长期存在的一个问题 生物学中的问题。我们最近发现了一种源自乳酸的新赖氨酸修饰，即赖氨酸乳酰化 (Kla)。 我们通过化学和生化方法全面验证了该 PTM。该 PTM 可以是 受到瓦尔堡效应衍生的乳酸的刺激，并且具有与广泛研究的不同的时间动态 赖氨酸乙酰化（Kac）。我们的表观遗传学研究表明，组蛋白 Kla 代表了一种新型代谢—— 调节表观遗传变化并有助于基因调控。我们假设组蛋白 Kla 通路 在分子上与 Kac 途径不同，有助于基因调控。因此我们建议 通过定义其关键调控元件来表征 Kla 途径：可以去除 Kla 途径的酶 修饰（或脱乳酰酶）及其对组蛋白和非组蛋白底物蛋白的靶标。我们还将 研究它们在毛囊干细胞 (HFSC) 循环行为的表观遗传调控中的作用，其中乳酸和 其调节酶发挥关键作用。我们将采用涉及化学生物学的综合策略， 酶学、定量蛋白质组学和生物化学方法。从这项研究中获得的知识将 可能会对我们对表观遗传学的理解产生广泛的影响，并将为研究 Kla 和 瓦尔堡效应。