Investigating histone glycation as a new dynamic epigenetic mark

研究组蛋白糖化作为新的动态表观遗传标记

• 批准号: 10408713
• 负责人: Yael E David-Shternberg
• 金额: $ 43.92万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408713
• 关键词: Affect; Architecture; Arginine; Biochemical Genetics; Biological; Biophysics; Blood Glucose; Cells; Chemicals; Chromatin; Chromatin Structure; Communication; DNA; Diabetes Mellitus; Disease; Epidemic; Epigenetic Process; Eukaryota; Gene Expression; Genes; Genetic Transcription; Higher Order Chromatin Structure; Histone Code; Histones; In Vitro; Link; Malignant Neoplasms; Methods; Modification; Molecular; Nature; PARK7 gene; Post-Translational Protein Processing; Process; Proteins; Reader; Research Project Grants; Resolution; Site; Stimulus; Transcriptional Regulation; Western World; Work; crosslink; glycation; histone modification; in vivo; insight; interdisciplinary approach; novel therapeutics; programs; repaired; response; therapeutic development

Project Summary The past decade has witnessed explosive advances in our understanding of how the organization of chromatin controls gene expression in eukaryotes. Much of the work delineating these mechanisms has contributed to the notion that a so-called ‘Histone Code,’ which refers to the landscape of histone post- translational modifications (PTMs), is a central determinant of a gene's potential to be activated or repressed in response to environmental stimuli. However, although detected in vivo, very little is known about how non-enzymatic covalent modifications (NECMs), such as glycation, affect the established cellular transcriptional program. We recently found that glycation, which is the hallmark of diabetes, accumulates on histones in a disease state-dependent manner (Zheng et al. Nature Communications, 2019). Using a variety of biophysical, biochemical and genetic methods we found that histone glycation disrupts regulatory histone PTMs as well as changes chromatin architecture in vitro and in cells by forming both histone-histone and histone-DNA crosslinks. Importantly, we identified a cellular regulatory response to this damage in the form of the deglycase DJ-1 as well as more recently, an arginine-specific deglycase, PAD4, which further demonstrates the crosstalk between histone glycation and other enzymatic PTMs (Zheng et al., in revision). In this proposal, we will take an interdisciplinary approach and leverage new chemical probes we developed to determine the sites of glycation on histones and their distribution within chromatin. In addition, we will perform a high-resolution analysis to identify the precise mechanistic effect histone glycation has on higher-order chromatin structure and the epigenetic landscape. Finally, we will investigate the cellular response to glycation by identifying “readers” and “erasers” of this new mark. Successful completion of this project is expected to yield a detailed molecular mechanism linking a new class of histone modifications to transcription regulation, thus providing essential insights into a fundamental biological problem and opening the door to new therapeutic avenues.

项目摘要 在过去十年中，我们对联合国如何发挥作用的理解取得了爆炸性进展。 染色质控制真核生物中的基因表达。描述这些机制的大部分工作 这一概念的贡献，所谓的“组蛋白代码”，这是指景观组蛋白后， 翻译修饰（PTM）是基因被激活或 对环境刺激的反应被压抑。然而，尽管在体内检测到， 关于非酶共价修饰（NECMs），如糖化，如何影响已建立的 细胞转录程序。我们最近发现糖基化，这是糖尿病的标志， 以疾病状态依赖的方式在组蛋白上积累（Zheng等，NatureCommunications， 2019年）。通过多种生物物理、生物化学和遗传学方法，我们发现组蛋白糖基化 破坏调节性组蛋白PTM，并通过形成 组蛋白-组蛋白和组蛋白-DNA交联。重要的是，我们发现了一种细胞调节反应， 对于这种以deglycase DJ-1形式的损害以及最近的，一种精氨酸特异性deglycase， PAD 4，进一步证明了组蛋白糖基化和其他酶促PTM之间的串扰 （Zheng等人，修订中）。在这项提案中，我们将采取跨学科的方法，利用新的 我们开发了化学探针来确定组蛋白上的糖化位点及其在组织中的分布， 染色质此外，我们将进行高分辨率分析，以确定精确的机械效应 组蛋白糖基化对高级染色质结构和表观遗传景观有影响。最后我们将 通过识别这种新标记的“读取器”和“擦除器”来研究细胞对糖化的反应。 该项目的成功完成有望产生一个详细的分子机制， 类组蛋白修饰转录调控，从而提供了重要的见解， 基本的生物学问题，并打开了新的治疗途径的大门。