Epigenetic control of meiotic recombination in mammals.
哺乳动物减数分裂重组的表观遗传控制。
基本信息
- 批准号:10088147
- 负责人:
- 金额:$ 19.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-05 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAneuploidyArchitectureBindingBiochemicalCellsChIP-seqCharacteristicsChimeric ProteinsChromatinChromatin ModelingChromatin Remodeling FactorChromatin StructureChromosome SegregationChromosomesCongenital AbnormalityDNA DamageDNA Double Strand BreakDNA RepairDNA SequenceEnzymesEpigenetic ProcessEventFrequenciesGametogenesisGeneticGenetic RecombinationGenome engineeringGenomic SegmentGerm CellsGonadal structureHistonesHumanImageInfertilityKnock-outKnockout MiceLeadLinkLocationMammalsMapsMeasuresMediatingMeiosisMeiotic RecombinationMethyltransferaseMitoticModelingMolecularMonitorMusOutcomePathway interactionsPhysical condensationPositioning AttributePost-Translational Protein ProcessingPregnancy lossProcessProtein SubunitsProteinsRecruitment ActivityResolutionRoleSiteSpermatocytesSpontaneous abortionTechniquesTestingTestisTimeWorkbasechromatin modificationchromatin remodelingds-DNAexperimental studygenetic approachgenome-widehistone modificationhomologous recombinationin vivonext generationpreventrecombinational repairrecruitrepairedresponsetool
项目摘要
Summary
Errors in homologous chromosome segregation during meiosis are the leading cause of birth defects,
spontaneous abortions, and contribute to infertility. Proper chromosome segregation requires pairwise
associations of maternal and paternal homologous chromosomes via crossovers, generated by homologous
recombination (HR)-mediated repair of double-strand DNA breaks (DSBs). Chromatin regulates the
accessibility to DSBs and, in turn, DSB repair. Chromatin remodeling complexes are required to repair DSBs in
meiotic and mitotic dividing cells, but how they control recruitment and activity of the HR repair machinery at
DSBs is unclear. The PBAF and BAF chromatin remodelers are connected to histone modifications occurring
at meiotic DSBs, and function in recruiting HR repair factors to DSBs. Our central hypothesis is that PBAF and
BAF link histone marks surrounding DSBs with the recruitment and activation of the meiotic HR machinery.
Our Specific Aims will test this hypothesis by addressing the following questions: (i) How do PBAF and BAF
regulate HR-mediated repair of DSB and, in turn, the number and position of HR intermediates and
crossovers? (ii) Do specific histone marks control the recruitment of PBAF/BAF and the HR machinery to HR
hotspot sites on meiotic chromosomes? (iii) Do changes in chromatin architecture around DSBs (i.e.
condensation) influence the efficiency of DSB repair? The first Aim will investigate the roles for the PBAF-
specific subunit Baf200, and the BAF-specific subunit Baf250A, in meiotic DSB repair, crossover formation,
and the association and disjunction of homologous chromosomes. We will employ established tools, such as
imaging and genetically modified mice, to discern the functions of PBAF and BAF as meiotic regulators. In Aim
2, we will elucidate the relationship between PBAF/BAF and HR repair by generating high-resolution genome-
wide binding profiles for PBAF/BAF and HR repair factors (Dmc1/Rad51) in mouse spermatocytes. To assess
whether PBAF/BAF are present and required for HR hotspot formation, we will generate and compare
genome-wide binding profiles of Dmc1/Rad51 in spermatocytes that lack Brg1, Baf200 (PBAF) or Baf250A
(BAF) to wild-type spermatocytes. To investigate whether PBAF/BAF are sufficient to influence local DSB
repair and crossover formation, we developed a lacO-lacI approach to target lacI fusion proteins (e.g. lacI-
Brg1) to ectopic lacO arrays. In Aim 3, we will determine which specific chromatin modifications around DSBs
are required to recruit PBAF/BAF and the HR machinery. These experiments will test our model that the
chromatin landscape around DSBs control PBAF/BAF recruitment, and illuminate how PBAF/BAF interact with
the HR pathway to influence DSB repair efficiency. Experiments in Aim 1 and 2 will also inform the molecular
aspects of how changes in chromatin structure influence meiotic recombination for the first time. The outcomes
are expected to be significant because they will unravel the epigenetic mechanisms underlying proper DNA
repair and homologous chromosome segregation during meiosis, which safeguards the next generation.
总结
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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Roberto Jose Pezza其他文献
Roberto Jose Pezza的其他文献
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{{ truncateString('Roberto Jose Pezza', 18)}}的其他基金
Development of a lacO/lacI based fluorescence reporter-operator system to study chromosome dynamics and double-strand break repair in mouse meiosis.
开发基于 lacO/lacI 的荧光报告操纵子系统,用于研究小鼠减数分裂中的染色体动力学和双链断裂修复。
- 批准号:
10674379 - 财政年份:2023
- 资助金额:
$ 19.5万 - 项目类别:
Development of a lacO/lacI based flourescence reporter-operator system to study chromosome dynamics in mice
开发基于 lacO/lacI 的荧光报告操纵子系统来研究小鼠染色体动力学
- 批准号:
10391570 - 财政年份:2021
- 资助金额:
$ 19.5万 - 项目类别:
Epigenetic control of meiotic recombination in mammals.
哺乳动物减数分裂重组的表观遗传控制。
- 批准号:
10194541 - 财政年份:2018
- 资助金额:
$ 19.5万 - 项目类别:
Epigenetic control of meiotic recombination in mammals - Equipment Supplement
哺乳动物减数分裂重组的表观遗传控制 - 设备补充
- 批准号:
10375710 - 财政年份:2018
- 资助金额:
$ 19.5万 - 项目类别:
The roles of Hop2 and Mndl in mouse meiotic homologous recombination
Hop2和Mndl在小鼠减数分裂同源重组中的作用
- 批准号:
8466514 - 财政年份:
- 资助金额:
$ 19.5万 - 项目类别:
The roles of Hop2 and Mndl in mouse meiotic homologous recombination
Hop2和Mndl在小鼠减数分裂同源重组中的作用
- 批准号:
8625783 - 财政年份:
- 资助金额:
$ 19.5万 - 项目类别:
The roles of Hop2 and Mndl in mouse meiotic homologous recombination
Hop2和Mndl在小鼠减数分裂同源重组中的作用
- 批准号:
9234554 - 财政年份:
- 资助金额:
$ 19.5万 - 项目类别:
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