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
- 来源:
- 关键词:Acetate-CoA LigaseAcetatesAcetyl Coenzyme AAcetylationAddressAlcohol consumptionAlcoholsApoptosisAutomobile DrivingBindingBiological ModelsBrainCaenorhabditis elegansChildChromatinChromosome PairingComplexCytologyDataDefectDiseaseDrosophila genusEmbryoEnvironmentEnvironmental ExposureEnvironmental ImpactEpigenetic ProcessEthanolEthanol MetabolismEventExposure toFetal Alcohol ExposureFetal Alcohol SyndromeFoundationsFunctional disorderFuture GenerationsGenerationsGeneticGenetic RecombinationGenomeGerm CellsGoalsHeritabilityHistone AcetylationHistonesHumanIncidenceKnowledgeLinkMammalsMapsMass Spectrum AnalysisMediatorMeiosisMemoryMetabolicMetabolic PathwayModelingModificationMolecularMorphologyMusNematodaNeurologicNuclearOrganismOutcomePathway interactionsPhysiologicalPost-Translational Protein ProcessingPregnancyRattusRegulationReportingReproductionReproductive HistoryResearchRodent ModelSeminalSymptomsTestingTissuesWestern EuropeWomanWorkalcohol effectalcohol exposurealcohol responsealcohol testingbehavioral impairmentdesignepigenomeepigenomicsfetalhistone modificationhomologous recombinationmodel organismneurobehavioralpharmacologicpreferenceprenatal exposureprogramsreproductivereproductive functionreproductive outcomestemtooltransgenerational epigenetic inheritancetransmission process
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.
项目摘要
本申请中提出的研究的总体目标是剖析遗传、表观遗传和
代谢程序编码并传递几代人的环境暴露记忆。在
在这种背景下,我们的目标是了解环境影响如何改变生物体的生殖程序
是什么使生殖系成为一个特别重要和敏感的目标,
暴露。
在哺乳动物中,子宫内乙醇暴露与一系列表征良好的形态学,
神经行为和生殖问题然而,越来越多的证据表明,
一些不利的生殖和神经功能的特点也可以在第三代检测到的生物
这表明了跨代效应。酒精也有明显的表观遗传影响,
有助于表观基因组的修饰。然而,尽管酒精的遗传效应
暗示着生殖细胞中所含信息的改变,目前还不清楚乙醇暴露的记忆是如何改变的。
在生殖细胞中开始,然后传递给后代。在这里,我们结合了联合收割机的易处理性和
模型系统的守恒性C.与国家的最先进的表观基因组分析,经典的遗传,
细胞学方法来阐明酒精暴露的记忆机制。我们的初步数据
表明乙醇暴露会导致强烈的跨代生殖和行为障碍。我们
还表明,与最近的哺乳动物研究一致,乙醇导致组蛋白乙酰化增加。
因此,我们假设乙醇暴露导致生殖细胞的跨代干扰,
通过改变种系表观基因组,特别是组蛋白乙酰化来发挥作用。我们的目标是
解决乙醇这些跨代影响的分子、代谢和表观遗传要求。
在aim1中,我们将建立在我们的初步繁殖数据上,通过经典遗传学工具进行询问
乙醇在生殖细胞凋亡和胚胎发育中的跨代增加的根源是减数分裂途径
杀伤力在目标2中,我们将通过质谱分析来检查80种不同组蛋白标记的调制
并测试组蛋白乙酰化的增加是否是一个必要的事件,
引发乙醇的跨代生殖效应。最后,在目标3中,我们将测试表观遗传
乙醇的影响的跨代传递的要求,也由切割和运行地图,
种系中组蛋白修饰的表观遗传景观的变化。
在目标完成时,我们将确定启动的分子基础,
乙醇的代际生殖结果的传递。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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
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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