Epigenetic control of spermatogonial stem cell self-renewal
精原干细胞自我更新的表观遗传控制
基本信息
- 批准号:10656855
- 负责人:
- 金额:$ 40.68万
- 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:2023-06-05 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAdultAnimalsBiologicalBiological AssayCellsChIP-seqChemicalsChromatinChromatin Remodeling FactorDataDissectionDonor personEpigenetic ProcessEquilibriumEtiologyFailureFoundationsGene ClusterGene ExpressionGene Transfer TechniquesGenerationsGenesGeneticGenetic TranscriptionGenetic studyGenomeGenomicsGerm CellsHistone H3Homeobox GenesImmunoprecipitationIn VitroInfertilityInformal Social ControlIntrinsic factorLifeMale InfertilityMass Spectrum AnalysisMediatingMethylationMethyltransferaseMolecularMusNucleosomesPlayProductionProteinsProteomicsRNA Polymerase IIRegulationReproductive MedicineResearchResolutionRoleSmall Interfering RNASpermatogenesisSpermatogoniaStem cell transplantTestisTranscriptional ActivationTransplantationZNF145 genecancer cellcytokineglial cell-line derived neurotrophic factorinhibitorinnovationinsightknock-downmalemale fertilitymultiple omicsmutantnovelprogenitorprogramsrecruitself-renewalsingle-cell RNA sequencingsperm cellstem cell biologystem cell divisionstem cell nichestem cell populationstem cell self renewalstem cellstranscription factortranscriptome sequencingtranslational applications
项目摘要
Project Summary
Males produce sperm continuously through adult life, driven by the renewal of spermatogonial stem cells
(SSCs). The long-term objective of this application is to determine the role of a novel epigenetic program that
we have recently identified in regulating the renewal of adult SSCs. SSCs can both self-renew and produce
progenitor spermatogonia that will differentiate to initiate spermatogenesis. The balance between SSC self-
renewal and differentiation is key for life-long production of sperm in adult males. Both SSC transplantation and
in vitro SSC cultures have enabled functional studies of SSC and allowed for advancement of translational
applications in animal transgenesis. However, while much is known about spermatogenesis, the regulation of
SSC self-renewal remains poorly understood. Stem cell renewal requires both stem cell-intrinsic factors and
external niche factors, only a handful of which have been identified (PLZF, RB, NANOS2, GDNF, ETV5, etc.).
Notably, their functions in SSC self-renewal have been revealed through genetic studies. Despite these
advances, the molecular biological control of SSC remains poorly understood. We have identified an
epigenetic factor DOT1L, the sole H3K79 methyltransferase, as a novel master regulator of mouse SSC self-
renewal. Moreover, by chemically inhibiting DOT1L, we were able to identify specific target genes that likely
contribute to SSC renewal. We propose an innovative multi-pronged (genetic, chemical, genomic, and
proteomic) approach to comprehensively elucidate this novel epigenetic program in SSCs. As failure in SSC
self-renewal leads to a lack of sperm production and thus male infertility, completion of this project will lay a
firm foundation for molecular dissection of SSC stem cell renewal and open new avenues of research in SSC
biology and reproductive medicine.
项目摘要
在精原干细胞更新的驱动下,雄性在整个成年期持续产生精子
(SSC)。本申请的长期目标是确定一种新的表观遗传程序的作用,
我们最近在调节成体SSC的更新中发现了这一点。SSCs既能自我更新,
将分化以启动精子发生的祖精原细胞。SSC自身之间的平衡
更新和分化是成年男性终生产生精子的关键。SSC移植和
体外SSC培养使SSC的功能研究成为可能,并允许促进SSC的翻译。
在动物转基因中的应用。然而,虽然对精子发生了解很多,但精子发生的调节
对南南合作的自我更新仍然知之甚少。干细胞更新需要干细胞内在因子,
外部生态位因素,其中只有少数已被确定(PLZF,RB,NANOS2,GDNF,ETV5等)。
值得注意的是,它们在SSC自我更新中的功能已通过遗传研究揭示。尽管有这些
尽管取得了一些进展,但对SSC的分子生物学控制仍然知之甚少。我们确定了一个
表观遗传因子DOT1L,唯一的H3K79甲基转移酶,作为小鼠SSC自我调节的一种新的主调节因子,
退款此外,通过化学抑制DOT1L,我们能够鉴定出可能
促进南南合作的复兴。我们提出了一个创新的多管齐下(遗传,化学,基因组,
蛋白质组学)方法来全面阐明SSCs中这种新的表观遗传程序。由于SSC失效,
自我更新导致精子生产不足,从而导致男性不育,该项目的完成将奠定一个
为SSC干细胞更新的分子解剖奠定坚实基础,并开辟SSC研究的新途径
生物学和生殖医学。
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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Peijing Jeremy Wang其他文献
Tracking LINE1 retrotransposition in the germline
- DOI:
10.1073/pnas.1709067114 - 发表时间:
2017-06 - 期刊:
- 影响因子:0
- 作者:
Peijing Jeremy Wang - 通讯作者:
Peijing Jeremy Wang
Peijing Jeremy Wang的其他文献
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{{ truncateString('Peijing Jeremy Wang', 18)}}的其他基金
Targeting the piRNA pathway and meiotic recombination for male contraception
针对男性避孕的 piRNA 途径和减数分裂重组
- 批准号:
8907516 - 财政年份:2015
- 资助金额:
$ 40.68万 - 项目类别:
Targeting the piRNA pathway and meiotic recombination for male contraception
针对男性避孕的 piRNA 途径和减数分裂重组
- 批准号:
9058577 - 财政年份:2015
- 资助金额:
$ 40.68万 - 项目类别:
Functions of MOV10L1 in piRNA biogenesis and germ cell development
MOV10L1 在 piRNA 生物发生和生殖细胞发育中的功能
- 批准号:
8292778 - 财政年份:2012
- 资助金额:
$ 40.68万 - 项目类别:
Functions of MOV10L1 in piRNA biogenesis and germ cell development
MOV10L1 在 piRNA 生物发生和生殖细胞发育中的功能
- 批准号:
8607581 - 财政年份:2012
- 资助金额:
$ 40.68万 - 项目类别:
Genetic Control of Retrotransposon Mobilization in the Mouse Germline
小鼠种系中逆转录转座子动员的遗传控制
- 批准号:
10447056 - 财政年份:2012
- 资助金额:
$ 40.68万 - 项目类别:
Functions of MOV10L1 in piRNA biogenesis and germ cell development
MOV10L1 在 piRNA 生物发生和生殖细胞发育中的功能
- 批准号:
8462286 - 财政年份:2012
- 资助金额:
$ 40.68万 - 项目类别:
Genetic Control of Retrotransposon Mobilization in the Mouse Germline
小鼠种系中逆转录转座子动员的遗传控制
- 批准号:
10200859 - 财政年份:2012
- 资助金额:
$ 40.68万 - 项目类别:
Genetic Control of Retrotransposon Mobilization in the Mouse Germline
小鼠种系中逆转录转座子动员的遗传控制
- 批准号:
10651822 - 财政年份:2012
- 资助金额:
$ 40.68万 - 项目类别:
Functions of MOV10L1 in piRNA biogenesis and germ cell development
MOV10L1 在 piRNA 生物发生和生殖细胞发育中的功能
- 批准号:
9026633 - 财政年份:2012
- 资助金额:
$ 40.68万 - 项目类别:
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