Systematic screening for new histone marks and studying their epigenetic function

表观遗传调控对不同的生物过程和疾病至关重要。翻译后 组蛋白中的修饰(PTM)通常被认为是一组主要的表观遗传标记， 为表观遗传学计划做出贡献，该计划规定了不同的DNA模板生物产出。我们队有 最近发现了九种新的组蛋白PTMS(赖氨酸丙酰化，赖氨酸丁酰化，赖氨酸 丙二酸化、赖氨酸琥珀酸化、赖氨酸戊二酸化、赖氨酸巴豆化、赖氨酸2-羟基异丁酰化、 赖氨酸3-羟丁酰化和赖氨酸苯甲酰化)。重要的是，我们和其他人展示了关键作用 通过揭示它们在基因转录控制中的独特功能，对这些新的PTM途径进行了研究 表达和细胞调节，并通过将它们与多种先天代谢性疾病联系起来。其中一些 组蛋白标记可以被其相应短链脂类的细胞水平刺激，因此表明 新陈代谢调控表观遗传学变化的新机制。这个应用程序基于巨大的 我们在早期研究中获得的关于鉴定和表征九种新类型的 组蛋白痕迹。我们假设在哺乳动物中还存在其他类型的未描述的组蛋白PTM 组蛋白。我们的假设得到了我们的初步数据的支持，这些数据在 组蛋白，其化学结构要么没有定义，要么仍有待充分验证。我们建议 使用集成方法，采用已在 我们团队的实验室，全面筛选新型的组蛋白PTM。我们队是最棒的 由于我们拥有的高超技能和众多技术，我们有能力找到这些组蛋白印记 ，以及我们在最近确定的新类型的 组蛋白痕迹。我们将首先全面筛选新类型的组蛋白标记，并通过两者验证它们 化学和生化方法。然后，我们将研究它们在精子发生过程中的表观遗传学作用。 新型组蛋白标记将极大地促进我们对染色质结构和功能的理解， 可能为表观遗传学研究开辟意想不到的途径，甚至可能转移当前研究的重点 表观遗传机制和疾病。

Epigenetic regulation is critical to diverse biological processes and diseases. Post-translational modifications (PTMs) in histones are generally considered to be a major group of epigenetic marks, contributing to the epigenetic program that dictates diverse DNA-templated biological outputs. Our team has recently identified nine types of novel histone PTMs (lysine propionylation, lysine butyrylation, lysine malonylation, lysine succinylation, lysine glutarylation, lysine crotonylation, lysine 2-hydroxyisobutyrylation, lysine 3-hydroxybutyrylation, and lysine benzoylation). Importantly, we and others demonstrated critical roles for these new PTM pathways by revealing their unique functions in the transcriptional control of gene expression and cellular regulation, and by linking them to multiple inborn metabolic diseases. Some of these histone marks can be stimulated by cellular levels of their corresponding short-chain lipids, thus suggesting new mechanisms for metabolism-regulated epigenetic changes. This application is based on the tremendous expertise we gained during our earlier studies on identification and characterization of nine novel types of histone marks. We hypothesize that additional, undescribed types of histone PTMs are present in mammalian histones. Our hypothesis is supported by our preliminary data identifying multiple undescribed PTMs in histones, the chemical structures of which are either undefined or remain to be fully validated. We propose to use an integrated approach, employing technologies that have been well established and fully validated in the laboratories of our team, to comprehensively screen for novel types of histone PTMs. Our team is best positioned to find these histone marks because of the tremendous skills and numerous technologies we have accumulated, and the high productivity we have demonstrated in our recent identification of the novel types of histone marks. We will first comprehensively screen for new types of histone marks and validate them by both chemical and biochemical methods. We will then investigate their epigenetic roles during spermatogenesis. New types of histone marks will significantly advance our understanding of chromatin structure and function, might open unforeseen avenues for epigenetic studies, and may even shift the focus of current research on epigenetic mechanisms and disease.