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

新出现的证据表明，能量代谢、代谢物和 表观遗传学。组蛋白(组蛋白标记)的翻译后修饰(PTM)(例如，赖氨酸乙酰化 (KAc)和甲基化(Kme))受新陈代谢调节，有助于表观遗传学 与细胞生理学和疾病相关的程序。然而，我们还不知道是否会有额外的 组蛋白PTM通路是否存在，以及它们是否能被不同的细胞代谢物调节。因此，化学和 代谢物介导的染色质变化的生物化学特征仍然很差。乳酸，一种广为人知的 细胞代谢物，可在某些细胞条件下(如缺氧)和在 沃堡效应，一种在不同癌症中最常见的观察结果，并与许多癌症有关 疾病。肿瘤组织中的乳酸浓度可升至20-40 mM。尽管这个化合物是 大约200年前被发现，它在生理上的非代谢功能(例如，缺氧、干细胞分化 和免疫反应)和疾病(如癌症和糖尿病)仍然未知，这是一个长期存在的 生物学中的一道题。我们最近发现了一种由乳酸衍生的新的赖氨酸修饰，赖氨酸乳糖化(KLA)。 我们通过化学和生化方法全面验证了这种PTM。此PTM可以是 在Warburg效应的刺激下衍生的乳酸，具有与广泛研究的不同的时间动力学 赖氨酸乙酰化(KAc)。我们的表观遗传学研究表明，组蛋白KLA代表了一种新的代谢类型-- 受调控的表观遗传学改变并有助于基因调控。我们假设组蛋白KLA途径 在分子水平上不同于KAc途径，参与基因调控。因此，我们建议 通过定义KLA途径的关键调节元件来表征KLA途径：可以移除 修饰(或去内切酶)，以及它们针对组蛋白和非组蛋白底物蛋白的靶点。我们还将 研究它们在毛囊干细胞(HfSCs)周期行为表观遗传调控中的作用 它的调节酶起着关键作用。我们将使用一种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产生广泛的影响，并将为研究KLA和 华宝效应。

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.