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.

新兴的证据表明能量代谢，代谢产物和 表观遗传学。组蛋白上的翻译后修饰（PTMS）（组蛋白“标记”）（例如，赖氨酸乙酰化 已知（KAC）和甲基化（KME）由代谢调节，有助于表观遗传学 与细胞生理和疾病相关的程序。但是，我们还不知道是否额外 Hisstone PTM途径存在，如果可以通过多种细胞代谢物调节它们。那，化学和 代谢物介导的染色质变化的生物化学的表征仍然很差。乳酸，众所周知 细胞代谢产物，可以在某些细胞条件（例如缺氧）和在 Warburg效应，这是潜水员癌中最常见的观察结果，与许多人相关 疾病。在癌组织中，乳酸浓度可以升至20-40毫米。虽然这种化合物是 发现〜200年前，其非代谢功能在生理学中（例如缺氧，干细胞分化） 和免疫响应）和疾病（例如癌症和糖尿病）尚不清楚，代表了长期存在的 生物学问题。我们最近发现了一种衍生的新赖氨酸修饰，赖氨酸乳酸化（KLA）。 我们通过化学和生化方法全面验证了该PTM。这个PTM可以是 由沃堡效应衍生的鞋底刺激，并具有与广泛研究的不同临时动力学 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 - 调节的表观遗传变化并有助于基因调节。我们假设组蛋白KLA途径 分子与KAC途径有所不同，并有助于基因调节。因此，我们建议 通过定义其关键调节元素来表征KLA途径：可以去除的酶 修饰（或可依dact酶）及其对组蛋白和非内酮底物蛋白的靶标。我们也会 研究它们在表观遗传调节中的作用 它的监管酶起关键作用。我们将使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 可能对我们对表观遗传学的理解有广泛的影响，并将为研究KLA和 Warburg效应。