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

基本信息

  • 批准号:
    10606928
  • 负责人:
  • 金额:
    $ 34.36万
  • 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:
    2023-06-01 至 2028-04-30
  • 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 dissect the genetic, epigenetic, and metabolic programs that encode and transmit a memory of environmental exposure for several generations. In that context, we aim to understand how environmental influences alter the reproductive program of organisms in a transgenerational fashion and what makes the germline a particularly important and sensitive target of exposures. In mammals, in utero ethanol exposure is associated with an array of well-characterized morphological, neurobehavioral, and reproductive issues. However, there is mounting evidence in a variety of model organisms that some adverse reproductive and neurological features are also detectable in the third generation following exposure indicating a transgenerational effect. Alcohol also has a clear epigenetic impact and directly contributes to the modification of the epigenome. Nevertheless, despite the fact that heritable effects of alcohol imply an alteration of the information contained in germ cells, it is unclear how the memory of ethanol exposure is initiated in the germline and then transmitted to future generations. Here, we combine the tractability and conservation of the model system C. elegans with state-of-the-art epigenomic analyses, classical genetic, and cytological approaches to shed light on the mechanisms of memory of ethanol exposure. Our preliminary data shows that ethanol exposure causes strong transgenerational reproductive and behavioral impairments. We also show that, in line with recent mammalian studies, ethanol causes an increase in histone acetylation. Thus, we hypothesize that ethanol exposure causes transgenerational perturbations of germline function by altering the germline epigenome, specifically histone acetylation. Our aims are designed to address the molecular, metabolic and epigenetic requirements for these transgenerational impacts of ethanol. In aim 1, we will build on our preliminary reproduction data to interrogate through classical genetics tools meiotic pathways at the root of ethanol's trans-generational increase in germline apoptosis and embryonic lethality. In aim 2, we will examine via mass spectrometry the modulation in 80 different histone marks stemming from direct ethanol exposure and test whether increased histone acetylation is a required event for the initiation ethanol's transgenerational reproductive effects. Finally, in aim 3, we will test the epigenetic requirement for the transgenerational transmission of ethanol's effects and also map by CUT&RUN the changes in the epigenetic landscape of histone modifications in the germline. At the completion of the aims, we will have identified the molecular underpinnings for the initiation and transmission of ethanol transgenerational reproductive outcomes.
项目总结

项目成果

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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

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
  • 批准号:
    10608433
  • 财政年份:
    2023
  • 资助金额:
    $ 34.36万
  • 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:
    $ 34.36万
  • 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:
    $ 34.36万
  • 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:
    $ 34.36万
  • 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:
    $ 34.36万
  • 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:
    $ 34.36万
  • 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:
    $ 34.36万
  • 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:
    $ 34.36万
  • 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:
    $ 34.36万
  • 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:
    $ 34.36万
  • 项目类别:

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钯催化的硅烷化乙酸烯丙酯新型有机转化的开发
  • 批准号:
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  • 财政年份:
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