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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

基本信息

批准号：
10670425
负责人：
Hao Duong
金额：
$ 17.75万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10670425
关键词：
Acceleration Biological Process Carcinogens Cardiovascular Diseases Cells Chromatin Chromatin Remodeling Factor Circadian Dysregulation Circadian Rhythms Circadian gene expression Classification Clock protein Co-Immunoprecipitations Complex DNA Methylation DNA Modification Methylases Dependence Developing Countries Development Disease Eating Ensure Foundations Funding Gene Expression Profile Genes Genetic Genetic Transcription Goals Grant Health Histones Hospitals Human Industrialization Industry International Agency for Research on Cancer Jet Lag Syndrome Knockout Mice Leisures Light Lysine Malignant Neoplasms Metabolic Diseases Methods Methylation Methyltransferase Modeling Molecular Molecular Genetics Multienzyme Complexes Nutrient Obesity Organism Pathologic Pathway interactions Pattern Periodicity Physiological Play Positioning Attribute Probability Process Protein Analysis Proteome Proteomics Publications RNA Interference Reporting Risk Role Schedule Sleep Solid Specificity Stimulus System Systems Integration Temperature Testing Therapeutic Time Urbanization Work career chromatin immunoprecipitation circadian circadian biology circadian pacemaker disadvantaged background experimental study histone methyltransferase malignant breast neoplasm methyl group mouse genetics mouse model next generation prevent recruit shift work statistics training opportunity transmission process

项目摘要

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/文摘