Role of epigenetic crosstalks in directing locus sensitivity to arsenic

表观遗传串扰在引导基因座对砷的敏感性中的作用

基本信息

  • 批准号:
    10608433
  • 负责人:
  • 金额:
    $ 53.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-25 至 2027-10-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The overarching goal of the research presented in this application is to understand what make some genomic loci more susceptible than others to environmental chemical perturbation. Using inorganic arsenic (iAs) as a model environmental toxicant of high human relevance, we will seek to mechanistically investigate how epigenetic crosstalks dictate locus-specific sensitivity to arsenic. iAs is a model epigenetic toxicant owing to its well described impact on global DNA hypomethylation coinciding with a reduction in the levels of the universal methyl donor SAM, used towards DNA and histone methylation. However, this model of epigenetic mechanism of iAs has been acknowledged as largely unsatisfactory since (1) even in the context of global DNA hypomethylation, some loci show hypermethylation while others show no change, and (2) the effect on histone methylation are non-uniform with many methylated histone marks showing increases while others show a decrease. Here, we propose to build on compelling preliminary data obtained through highly quantitative Mass Spec and metabolomic studies that show that in mouse ESCs, at levels where sodium arsenite does not cause a significant increase in ROS levels, a pronounced decrease in SAM, DNA methylation, and in several histone marks, such as H3K36me2/3, are observed. However, H3K27me3 levels are increased while H3K9me3 levels are unchanged. Furthermore, RNA-seq studies revealed even in the context of profound transcriptional changes, repetitive elements that are repressed by deposition of H3K9me3 remain transcriptionally silenced following sodium arsenite exposure. Thus, we hypothesize that epigenetic crosstalks can differentially compete for the reduced SAM pool caused by iAs exposure, thereby driving locus sensitivity. To test this hypothesis, we will use mouse ESCs where crosstalks are well characterized. In aim 1, we will characterize the genome-wide changes in DNA methylation and in 3 distinct histone PTMs. We will also test whether these epigenetic alterations caused by iAs require the metabolic activity of the arsenic methyltransferase AS3MT. In aim 2, we will use a combination of knock-down, over-expression, and profiling approaches to mechanistically interrogate in the context of arsenic exposure the role of the well-characterized crosstalks between DNA methylation and histone PTMs at distinct genomic loci. Finally, in aim 3, we will examine the reprogrammability of arsenic-induced epigenetic alterations as ESCs are differentiated into early stage germ cells and go through profound waves of epigenetic remodeling. At the completion of these aims, we will have established the comprehensive profile of changes in DNA methylation and 4 histone PTMs following arsenic exposure. We will also have determined how epigenetic crosstalks mediate locus-specific sensitivity to arsenic and their ability to be reprogrammed in PGCs. This work will firmly establish the central role of epigenetic crosstalks in the response to environmental insults.
项目总结

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Patrick Allard其他文献

Patrick Allard的其他文献

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{{ truncateString('Patrick Allard', 18)}}的其他基金

Epigenetic and metabolic mechanisms of environmentally-induced transgenerational germline dysfunction
环境诱导的跨代种系功能障碍的表观遗传和代谢机制
  • 批准号:
    10606928
  • 财政年份:
    2023
  • 资助金额:
    $ 53.47万
  • 项目类别:
E-Cigarette Vaping during Pregnancy and Lactation, Germ Cell Epigenetic Memory, and Transgenerational Asthma
怀孕和哺乳期电子烟、生殖细胞表观遗传记忆和跨代哮喘
  • 批准号:
    10428619
  • 财政年份:
    2020
  • 资助金额:
    $ 53.47万
  • 项目类别:
E-Cigarette Vaping during Pregnancy and Lactation, Germ Cell Epigenetic Memory, and Transgenerational Asthma
怀孕和哺乳期电子烟、生殖细胞表观遗传记忆和跨代哮喘
  • 批准号:
    10657604
  • 财政年份:
    2020
  • 资助金额:
    $ 53.47万
  • 项目类别:
Mechanisms of environmental epigenetic disruption and memory of exposure in germ cells
环境表观遗传破坏机制和生殖细胞暴露记忆
  • 批准号:
    10112905
  • 财政年份:
    2017
  • 资助金额:
    $ 53.47万
  • 项目类别:
Germ Cell-Mediated Epigenetic Memory of Ethanol Exposure
生殖细胞介导的乙醇暴露表观遗传记忆
  • 批准号:
    9235656
  • 财政年份:
    2017
  • 资助金额:
    $ 53.47万
  • 项目类别:
Mechanisms of environmental epigenetic disruption and memory of exposure in germ cells
环境表观遗传破坏机制和生殖细胞暴露记忆
  • 批准号:
    9217336
  • 财政年份:
    2017
  • 资助金额:
    $ 53.47万
  • 项目类别:
Student-to-Scientist Bridge Program in Environmental Health Science (S2S Bridge)
环境健康科学学生与科学家的桥梁计划(S2S Bridge)
  • 批准号:
    9044779
  • 财政年份:
    2015
  • 资助金额:
    $ 53.47万
  • 项目类别:
Student-to-Scientist Bridge Program in Environmental Health Science (S2S Bridge)
环境健康科学学生与科学家的桥梁计划(S2S Bridge)
  • 批准号:
    9247182
  • 财政年份:
    2015
  • 资助金额:
    $ 53.47万
  • 项目类别:
Design of a high-throughput screen for chemicals that cause meiotic aneuploidy
导致减数分裂非整倍体化学物质的高通量筛选设计
  • 批准号:
    8586524
  • 财政年份:
    2012
  • 资助金额:
    $ 53.47万
  • 项目类别:
Design of a high-throughput screen for chemicals that cause meiotic aneuploidy
导致减数分裂非整倍体化学物质的高通量筛选设计
  • 批准号:
    8775669
  • 财政年份:
    2012
  • 资助金额:
    $ 53.47万
  • 项目类别:

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  • 批准号:
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