Potential Role of Compass H3K4 Methyltransferase Complexes in Environmental Circadian-Alignment

Compass H3K4 甲基转移酶复合物在环境昼夜节律调整中的潜在作用

• 批准号: 10799011
• 负责人: Hao Duong
• 金额: $ 9.63万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10799011
• 关键词: Biological Process; Cardiovascular Diseases; Cells; Chromatin; Circadian Dysregulation; Circadian Rhythms; Complex; DNA Methylation; DNA Modification Methylases; Development; Disease; Ensure; Foundations; Gene Expression Profile; Genes; Genetic Transcription; Health; Histones; Human; Jet Lag Syndrome; Light; Lysine; Malignant Neoplasms; Metabolic Diseases; Methylation; Methyltransferase; Molecular; Nutrient; Obesity; Organism; Pathologic; Periodicity; Physiological; Play; Process; Protein Analysis; Proteomics; Risk; Role; System; Temperature; Therapeutic; circadian; histone methyltransferase; malignant breast neoplasm; methyl group; prevent; recruit; shift work

Summary/Abstract Environmental-Circadian Disruption such as shiftwork and Jetlag imposes major risk on human health in the U.S. and abroad. It increases the risk of many metabolic and cardiovascular disorders and cancers and effects over 16% of the U.S. workforce. Yet, the molecular underpinnings of this process remain unclear. In a proteomic analysis of proteins interacting with Cry1, we identified 10 components of COMPASS complexes. These enzymatic complexes regulate gene transcription by catalyzing the addition of methyl groups to lysine 4 of histone 3 (H3K4mes) of local chromatin. Interestingly, these chromatin marks respond to environmental circadian entrainment information such as light, temperature or nutrients. They also happen in a circadian rhythmic manner and modulate DNA methylation, a determinant of gene transcription and disease development. Furthermore, functional perturbations of various COMPASS components were also implicated in pathological conditions associated with disharmony of environmental and circadian cycles such as breast cancer and obesity. We thus hypothesize that COMPASS complexes play a key role in environmental-circadian alignment. Under environmental-circadian alignment condition, COMPASS complexes are recruited by Cry1 to rhythmically methylate local H3K4s, which prevent recruitment of DNA methyltransferases resulting in perturbations of DNA methylation and expression of core clock gene(s). This methylation cascade modulates the circadian pattern of gene expression, ensuring alignment of the circadian system with daily environmental cycles. The methylation cascade fails to initiate when internal circadian system mis-aligns with external environmental cycles, leading to perturbation of the homeostatic state of cells and development of disorders. We will investigate this hypothesis by pursuing the following initial aims: 1: To characterize circadian Cry1::COMPASS interaction; Aim 2: To investigate the role of COMPASS complexes in methylation of core clock genes; Aim 3: To study the effects of environmental- circadian disruption on COMPASS function. The results of this project might unveil the molecular mechanism of a fundamental biological process: synchronization of daily internal physiological rhythms with external environmental cycles. They might also illuminate the nuts and bolts of disorders associated with shiftwork.

摘要/摘要 环境-昼夜节律中断，如倒班和时差，给 美国和国外的人类健康。它增加了许多代谢和心血管疾病的风险 疾病、癌症和影响超过16%的美国劳动力。然而，分子 这一过程的基础仍不清楚。 在对与Cry1相互作用的蛋白质进行的蛋白质组学分析中，我们确定了10种成分 罗盘情结。这些酶复合体通过催化作用调节基因转录。 在组蛋白3(H3K4mes)的赖氨酸4上加甲基，形成局部染色质。有趣的是， 这些染色质标记对环境昼夜节律夹带信息做出反应 光、温度或营养物质。它们也以昼夜节律的方式发生并调节 DNA甲基化，基因转录和疾病发展的决定因素。此外， 不同指南针部件的功能紊乱也与病理有关 与环境和生物钟周期不协调有关的状况，如乳房 癌症和肥胖症。因此，我们假设COMPASS复合体在 环境-昼夜节律对齐。在环境-昼夜节律对齐条件下， COMPASS复合体被Cry1招募来有节奏地甲基化局部H3K4，从而防止 DNA甲基转移酶的募集导致DNA甲基化和 核心时钟基因的表达(S)。这种甲基化级联反应调节了 基因表达，确保昼夜节律系统与日常环境周期保持一致。这个 当内部昼夜节律系统与外部昼夜节律系统错位时，甲基化级联无法启动 环境循环，导致细胞的动态平衡状态和发育受到干扰 精神错乱。我们将通过追求以下初步目标来研究这一假设：1. 描述昼夜节律：：COMPASS相互作用；目标2：研究COMPASS的作用 核心时钟基因甲基化中的复合体；目标3：研究环境- 指南针功能的昼夜节律紊乱。 这一项目的结果可能会揭示一种基本生物学的分子机制 过程：日常内部生理节律与外部环境周期同步。 它们还可能阐明与倒班工作相关的疾病的具体细节。