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：
10623277
负责人：
Hening Lin
金额：
$ 67.68万
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/10623277
关键词：
Acetylation Acetyltransferase Area Behavior Biochemical Biochemistry Bioinformatics Biology Cell physiology Cells ChIP-seq 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 Resting Phase Role Site Skin Substrate Specificity System Testing Tissues Transcriptional Regulation Warburg Effect Western Blotting adult stem cell 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.

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。组蛋白的表观遗传学（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计划但是，我们还不知道是否还有其他计划。组蛋白 PTM 途径存在，并且它们是否可以通过多种细胞代谢物进行调节。代谢物介导的染色质变化的生物化学仍然知之甚少，乳酸是一种广为人知的物质。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观察结果，并与许多癌症相关尽管这种化合物在癌症组织中可能会升高至 20-40 mM。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。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 - 我们研究组蛋白 Kla 通路调控表观遗传变化并有助于基因调控。在分子上与 Kac 途径不同，并且有助于基因调控。通过定义其关键调控元件来表征 Kla 途径：可以去除 Kla 途径的酶我们还将讨论修饰（或脱乳酰酶）及其对组蛋白和非组蛋白底物蛋白的作用。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，其中乳酸和它的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，从这项研究中获得的知识将包括酶学、定量蛋白质组学和生物化学方法。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。