Mechanisms of hydrogen-sulfide effects on the epigenetic landscape

硫化氢对表观遗传景观的影响机制

• 批准号: 8814466
• 负责人: Dana L Miller
• 金额: $ 42.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814466
• 关键词: Acute; Affect; Aging; Anaerobic Bacteria; Animal Model; Animals; Behavior; Biology; Breathing; Caenorhabditis elegans; Carbon Monoxide; Cardiovascular system; Cause of Death; Cessation of life; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Chronic; Communities; Complex; Data; Deposition; Disease susceptibility; Dose; Environment; Environmental Health; Enzymes; Epigenetic Process; Exposure to; Functional disorder; Gases; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Screening; Genetic Transcription; Genomics; Human; Hydrogen Sulfide; Hypoxia Inducible Factor; Ischemia; Laboratories; Learning; Lesion; Long-Term Effects; Longevity; Mammals; Maps; Measures; Mediating; Memory; Mentors; Metabolic; Molecular; Molecular Genetics; Mutation; Neurologic; Occupational; Occupational Exposure; Pathway interactions; Physiology; Principal Investigator; Proteins; Public Health; Reporting; Research; Research Personnel; Research Project Grants; Role; Signal Pathway; Stimulus; Stress; Sulfides; System; Testing; Therapeutic; Tissues; Toxic Environmental Substances; Toxin; Translating; Universities; Washington; Work; base; career; chromatin remodeling; clinical application; drug efficacy; gene cloning; genetic approach; imprint; in vivo; insight; mutant; programs; promoter; public health relevance; respiratory; response; transcription factor; transcriptome sequencing

 DESCRIPTION (provided by applicant): Exposure to environmental toxins can elicit epigenetic changes with the long-term effect to modulate transcription, leading to long-lasting effects that alter disease susceptibility, drug efficacy, and even the rate of aging. The mechanisms by which environmental conditions are translated into changes in the epigenetic landscape are poorly understood. The investigators have discovered a new epigenetic transcriptional memory in response to H2S exposure in C. elegans. H2S is a common environmental toxin, and is the second most common cause of occupational deaths from inhaled gas, behind only carbon monoxide. In this research project, the investigators will leverage the power of C. elegans genetics to test the hypothesis that environmental toxins such as H2S alter the epigenetic landscape. They will measure transcriptional responses associated with specific H2S exposures that have differential phenotypic effects, and will delineate how epigenetic effects associated with the response to H2S alters transcriptional response to subsequent toxin exposure. Their preliminary data show that the conserved ATP- dependent chromatin-remodeling enzyme SWI/SNF is required for the long-lasting memory of H2S. The investigators will measure the genomic localization of SWI/SNF components and determine when and where the complex is required to test the hypothesis that chromatin remodeling underlies the transcriptional memory of H2S. Finally, the investigators have isolated new mutations that disrupt the normal epigenetic response to H2S. They will use the power of C. elegans molecular and genetic biology to identify the genes and pathways that mediate the long- lasting effects of H2S exposure. Together, these studies will reveal fundamental features of how cellular responses integrate with epigenetic factors to coordinate long-term effects of environmental stimuli in animals. Moreover, this research project will facilitate career enhancement and mentoring that will fully integrate the Principal Investigator's lab with the excellent environmental health science community at the University of Washington.

 描述（由申请人提供）：暴露于环境毒素可引起表观遗传变化，具有调节转录的长期效应，导致改变疾病易感性、药物疗效甚至衰老速率的长期效应。环境条件转化为表观遗传景观变化的机制知之甚少。研究人员发现了一种新的表观遗传转录记忆，以响应C.优雅的硫化氢是一种常见的环境毒素，是吸入气体导致职业死亡的第二大常见原因，仅次于一氧化碳。在这个研究项目中，研究人员将利用C。elegans遗传学来检验环境毒素如H2S改变表观遗传景观的假设。他们将测量与具有不同表型效应的特定H2S暴露相关的转录反应，并将描述与H2S反应相关的表观遗传效应如何改变随后毒素暴露的转录反应。他们的初步数据表明，保守的ATP依赖性染色质重塑酶SWI/SNF是持久记忆H2S所必需的。研究人员将测量SWI/SNF组分的基因组定位，并确定何时何地需要复合物来检验染色质重塑是H2S转录记忆基础的假设。最后，研究人员已经分离出了新的突变，这些突变破坏了对H2S的正常表观遗传反应。他们将使用C的力量。线虫分子和遗传生物学，以确定基因和途径，介导的长期持久影响的硫化氢暴露。总之，这些研究将揭示细胞反应如何与表观遗传因素整合以协调环境刺激对动物的长期影响的基本特征。此外，该研究项目将促进职业发展和指导，将充分整合首席研究员的实验室与优秀的环境健康科学界在华盛顿大学。