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: 9181407
• 负责人: Dana L Miller
• 金额: $ 44.56万
• 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/9181407
• 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 Screening; Genetic Transcription; Genomics; Human; Hydrogen Sulfide; Hypoxia Inducible Factor; Industrialization; 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; Phenotype; Physiology; Principal Investigator; 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; career; chromatin remodeling; clinical application; drug efficacy; gene cloning; gene product; genetic approach; hypoxia inducible factor 1; imprint; in vivo; insight; mutant; programs; promoter; public health relevance; respiratory; response; survival prediction; 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(申请人提供)：暴露在环境毒素下可引起表观遗传变化，其长期效应是调节转录，导致长期效应，从而改变疾病易感性、药物疗效，甚至衰老速度。环境条件转化为表观遗传景观变化的机制还知之甚少。研究人员在线虫体内发现了一种新的表观遗传转录记忆，以应对硫化氢的暴露。硫化氢是一种常见的环境毒素，是职业性吸入气体死亡的第二大原因，仅次于一氧化碳。在这项研究项目中，研究人员将利用线虫遗传学的力量来测试环境毒素(如硫化氢)改变表观遗传格局的假设。他们将测量与特定的硫化氢暴露相关的转录反应，这些反应具有不同的表型效应，并将描绘与对硫化氢的反应相关的表观遗传效应如何改变对后续毒素暴露的转录反应。他们的初步数据表明，保守的依赖于ATP的染色质重塑酶SWI/SNF是长时间记忆硫化氢所必需的。研究人员将测量SWI/SNF组件的基因组定位，并确定何时何地需要该复合体来检验染色质重塑是硫化氢转录记忆的基础这一假设。最后，研究人员分离出了扰乱对硫化氢的正常表观遗传反应的新突变。他们将利用线虫分子和遗传生物学的力量来确定调节硫化氢暴露的长期影响的基因和途径。总之，这些研究将揭示细胞反应如何与表观遗传因素相结合，以协调环境刺激对动物的长期影响的基本特征。此外，这一研究项目将促进职业发展和指导，将首席研究员的实验室与华盛顿大学优秀的环境健康科学界充分结合起来。