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 环境环境破坏（例如Shiftwork和Jetlag）对 美国和国外的人类健康。它增加了许多代谢和心血管的风险 疾病和癌症以及超过16％的美国劳动力的影响。但是，分子 此过程的基础尚不清楚。 在与Cry1相互作用的蛋白质蛋白质分析中，我们确定了10个成分 指南针复合体。这些酶复合物通过催化调节基因转录 将甲基添加到局部染色质组蛋白3（H3K4ME）的赖氨酸4中。有趣的是， 这些染色质标记对环境昼夜节律响应，例如 轻，温度或营养。它们也以昼夜节律的方式发生并调制 DNA甲基化，基因转录和疾病发育的决定因素。此外， 各种指南针组件的功能扰动也与病理有关 与环境和昼夜节车（例如乳房）的不和谐有关的条件 癌症和肥胖。因此，我们假设指南针综合体在 环境环境对齐。在环境环境对准条件下， Cry1招募了指南针络合物，以节奏地甲基化局部H3K4，这阻止了 募集DNA甲基转移酶，导致DNA甲基化和 核钟基因的表达。这种甲基化级联调节 基因表达，确保昼夜节律与每日环境周期的对齐。这 当内部昼夜节系统与外部错误一致时，甲基化级联反应无法启动 环境周期，导致细胞和发育的稳态状态扰动 疾病。我们将通过追求以下初始目标来调查这一假设：1： 表征昼夜节律cry1 ::指南针互动；目标2：调查指南针的作用 核心时钟基因甲基化的复合物；目标3：研究环境的影响 - 指南针功能的昼夜节律破坏。 该项目的结果可能会揭示基本生物学的分子机制 过程：每日内部生理节奏与外部环境周期的同步。 他们还可能阐明与轮班工作相关的疾病的坚果和螺栓。