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
基本信息
- 批准号:9235656
- 负责人:
- 金额:$ 21.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-16 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlcohol consumptionAlcoholsAreaBiological ModelsCaenorhabditis elegansCell DeathCell Differentiation processCell modelCell physiologyCellsChIP-seqChromatinComplexCongenital AbnormalityDNADNA MethylationDevelopmentDiseaseDoseEmbryoEmbryonic DevelopmentEpigenetic ProcessEthanolEtiologyExhibitsExposure toFailureFetal Alcohol Spectrum DisorderFetal GrowthFetal LiverFoundationsGenerationsGenesGeneticGenetic ModelsGenomeGerm CellsGoalsHealthHeartHeritabilityHistonesHomeostasisHumanHypogonadismImmunofluorescence ImmunologicIn VitroInfertilityKineticsLeadLinkLungMammalsMeasuresMediatingMemoryModelingModificationMolecularMonitorMusNatureNematodaNeuronsOrganismOutcomePatternPharmaceutical PreparationsPhenotypePhysiologicalRegulationRepetitive SequenceReportingReproductionReproductive HealthResearchRetroelementsRetrotransposonRoleSomatic CellStem cellsSterilityStructure of primordial sex cellTimeTissuesToxic effectUnited StatesUp-RegulationWorkalcohol effectalcohol exposurealcohol researchalcohol sensitivitycell typedemethylationembryonic stem cellepigenetic memoryepigenomeexperimental studygenome-widehistone modificationinfant deathinnovationnovelprogramsreproductive
项目摘要
PROJECT SUMMARY/ABSTRACT
The long-term goal of this project is to identify the molecular components underlying the
heritability of ethanol's effect on germ cells. Germ cells are the bridge between generations and
their integrity is paramount to the health and viability of all organisms. As such, the
dysregulation of germ cells function significantly contributes to infertility and is also the leading
cause of birth defects and infant deaths in the United States. Remarkably, although there is a
clear contribution of ethanol to the etiology of human germ cell errors, its mechanisms of action,
especially at embryonic stages of germ cell differentiation, have remained elusive.
One largely under-explored area of ethanol's effect is the perturbation of germ cells'
epigenome. This is particularly significant as (1) ethanol has been shown to strongly impact the
epigenome of diverse somatic cell types and (2) embryonic germ cells are vulnerable to
epigenetic-modifiers as they undergo an extensive remodeling of their chromatin which includes
genome-wide demethylation and the establishment of a complex pattern of histone
modifications. The failure to properly regulate these histone marks leads to spurious repetitive
element expression, germ cell death and infertility. Furthermore, preliminary evidence gathered
in the powerful genetic model system C. elegans indicates that exposure to ethanol leads to a
heritable desilencing of normally repressed chromatin in germ cells.
Here, we propose to leverage two complementary germ cell models, the nematode C.
elegans and in vitro generated mouse germ cells, to elucidate the molecular nature of ethanol's
epigenetic alterations. We will achieve this goal by first demonstrating the sensitivity of germ
cells to physiological ethanol concentrations elicited from direct or ancestral exposure. We will
then thoroughly characterize the epimutations arising from ethanol exposure on stem cell-
derived mouse primordial germ cells at the time of their epigenetic remodeling.
We expect this research to provide a much-needed comprehensive examination of the
epigenetic changed that are correlated with a particular sensitivity of early germ cells to ethanol.
项目总结/摘要
该项目的长期目标是确定潜在的分子组成,
乙醇对生殖细胞影响的遗传性。生殖细胞是世代之间的桥梁,
它们的完整性对所有生物体的健康和生存能力至关重要。因此,
生殖细胞功能失调是导致不育的主要原因,
出生缺陷和婴儿死亡的原因在美国。值得注意的是,虽然有一个
乙醇对人类生殖细胞错误病因学的明确贡献,其作用机制,
特别是在生殖细胞分化的胚胎阶段,仍然是难以捉摸的。
乙醇影响的一个很大程度上未被探索的领域是对生殖细胞功能的干扰。
表观基因组这是特别重要的,因为(1)乙醇已经显示出强烈影响
不同体细胞类型的表观基因组和(2)胚胎生殖细胞容易受到
表观遗传修饰剂,因为它们经历了广泛的染色质重塑,包括
全基因组去甲基化和组蛋白复杂模式的建立
修改.不能正确调节这些组蛋白标记导致了虚假的重复
元件表达、生殖细胞死亡和不育。此外,初步证据显示,
在强大的遗传模型系统C. elegans表明,接触乙醇会导致
在生殖细胞中正常被抑制的染色质的可遗传的去沉默。
在这里,我们建议利用两个互补的生殖细胞模型,线虫C。
elegans和体外产生的小鼠生殖细胞,以阐明乙醇的分子性质
表观遗传改变我们将通过首先证明细菌的敏感性来实现这一目标。
细胞生理乙醇浓度引起的直接或祖先的曝光。我们将
然后彻底描述干细胞上乙醇暴露引起的表突变,
衍生的小鼠原始生殖细胞在其表观遗传重塑的时候。
我们希望这项研究能够提供一个急需的全面检查,
表观遗传变化与早期生殖细胞对乙醇的特殊敏感性有关。
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:
$ 21.59万 - 项目类别:
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
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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
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$ 21.59万 - 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
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$ 21.59万 - 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:
$ 21.59万 - 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:
$ 21.59万 - 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)
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9044779 - 财政年份:2015
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Student-to-Scientist Bridge Program in Environmental Health Science (S2S Bridge)
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- 批准号:
9247182 - 财政年份:2015
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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
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- 资助金额:
$ 21.59万 - 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
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8775669 - 财政年份:2012
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