pRB and changes in the chromatin landscape during myogenic differentiation
pRB 和生肌分化过程中染色质景观的变化
基本信息
- 批准号:8665617
- 负责人:
- 金额:$ 9.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAffectBindingBypassCell CycleChromatinComplexCoupledDNADNA MethylationDataData SetDepositionEnabling FactorsEnzymesEpigenetic ProcessEventExcisionFundingGene ExpressionGene Expression RegulationGene SilencingGene TargetingGenesGoalsGrowthHistone DeacetylaseHistone H2BHistone H3HistonesHurricaneImmunoprecipitationInvestigationLeadLinkLysineMaintenanceMapsMediatingMethodsMethylationMethyltransferaseMolecular ProfilingMono-SMuscleMuscle FibersMyoblastsPRC1 ProteinParentsPhasePlayPolycombProcessProteinsRBL2 geneRecruitment ActivityRegulationRegulator GenesRetinoblastomaRetinoblastoma ProteinRoleSignal TransductionStagingStructureSystemTestingTimeTumor Suppressor ProteinsWithdrawalWorkbasecdc Geneschromatin immunoprecipitationchromatin modificationgene repressiongenome-widehistone methyltransferasehistone modificationmutantmyogenesisnovelresearch study
项目摘要
We have begun a systematic investigation of all chromatin modifications associated with myogenic
differentiation using a combination of ChIP-sequencing (ChIP-seq) and expression profiling. Here, we propose
the following aims to further dissect the mechanisms underlying pocket protein involvement in cell cycle exit
and differentiation. In our first Aim, we will examine gene regulation during myogenic differentiation by
specifically focusing on the role of histone H2B ubiquitylation (H2BUb) during differentiation. We will examine
the extent of histone cross-talk in myotubes and investigate the impact of ablating RNF20, the enzyme
responsible for H2B ubiquitylation, on differentiation. Remarkably, we have found that H2BUb essentially
disappears during differentiation, and therefore we will examine the underlying mechanistic basis for myotubespecific
loss of H2Bub. In our second Aim, we will examine the genome-wide role of pRB and co-repressors in
directing chromatin modifications. We will first perform ChIP-seq on pRB and p130 in differentiated myotubes,
enabling us to identify regions bound by these factors. We will also perform expression profiling after removal
of pRB or p130 from myotubes. By merging these data, we will determine how chromatin modifications and
gene expression are affected by loss of pocket proteins. Using our extensive ChIPseq data as a guide, we will
test the hypothesis that pRB directs tri-methylation of H3K27 (H3K27me3) and ask whether Polycomb
repressive complex (PRC2) is involved and to what extent. We will examine whether Ezh2 or an alternative
histone methyltransferase (HMT), such as Ezh1, may be involved in H3K27me3 deposition. We will determine
whether pRB influences the recruitment of either or both HMTs. The acquisition of our extensive ChIP-seq
dataset allows us an unprecedented ability to examine on a genome-wide scale the relationship between pRB
binding, chromatin modifications, and gene expression in a developmentally relevant setting, thereby
enhancing our understanding of regulatory controls that are essential for both reversible and permanent gene
silencing, withdrawal from the cell cycle, and muscle differentiation. Progress on both Aims was impacted by
Hurricane Sandy. Funds are requested to continue the Aims listed above.
我们已经开始对与肌源性相关的所有染色质修饰进行系统研究
使用 ChIP 测序 (ChIP-seq) 和表达谱分析相结合进行分化。在此,我们建议
以下旨在进一步剖析口袋蛋白参与细胞周期退出的机制
和差异化。在我们的第一个目标中,我们将通过以下方式检查生肌分化过程中的基因调控:
特别关注组蛋白 H2B 泛素化 (H2BUb) 在分化过程中的作用。我们将检查
肌管中组蛋白串扰的程度并研究消除 RNF20(酶)的影响
负责 H2B 泛素化和分化。值得注意的是,我们发现 H2BUb 本质上
在分化过程中消失,因此我们将检查肌管特异性的潜在机制基础
H2Bub 的损失。在我们的第二个目标中,我们将研究 pRB 和共阻遏物在全基因组范围内的作用。
指导染色质修饰。我们将首先对分化肌管中的 pRB 和 p130 进行 ChIP-seq,
使我们能够确定受这些因素约束的区域。我们还将在删除后进行表达分析
来自肌管的 pRB 或 p130。通过合并这些数据,我们将确定染色质如何修饰和
基因表达受到口袋蛋白丢失的影响。使用我们广泛的 ChIPseq 数据作为指导,我们将
检验 pRB 指导 H3K27 (H3K27me3) 三甲基化的假设,并询问 Polycomb 是否
抑制复合体 (PRC2) 参与其中以及参与程度如何。我们将检查 Ezh2 或替代品
组蛋白甲基转移酶 (HMT),例如 Ezh1,可能参与 H3K27me3 沉积。我们将确定
pRB 是否影响其中一个或两个 HMT 的招募。收购我们广泛的 ChIP-seq
数据集使我们能够以前所未有的能力在全基因组范围内检查 pRB 之间的关系
在发育相关的环境中结合、染色质修饰和基因表达,从而
增强我们对可逆基因和永久基因都至关重要的监管控制的理解
沉默、退出细胞周期和肌肉分化。这两个目标的进展受到以下因素的影响
飓风桑迪。需要资金来继续实现上述目标。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Brian D Dynlacht其他文献
Brian D Dynlacht的其他文献
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{{ truncateString('Brian D Dynlacht', 18)}}的其他基金
Tubulin modifications and cytoskeletal alterations in aging
衰老过程中的微管蛋白修饰和细胞骨架变化
- 批准号:
10590128 - 财政年份:2023
- 资助金额:
$ 9.37万 - 项目类别:
Exploring networks underlying muscle stem cell identity - Resubmission - 1
探索肌肉干细胞身份背后的网络 - 重新提交 - 1
- 批准号:
10406897 - 财政年份:2021
- 资助金额:
$ 9.37万 - 项目类别:
Exploring networks underlying muscle stem cell identity - Resubmission - 1
探索肌肉干细胞身份背后的网络 - 重新提交 - 1
- 批准号:
10116803 - 财政年份:2021
- 资助金额:
$ 9.37万 - 项目类别:
Exploring networks underlying muscle stem cell identity - Resubmission - 1
探索肌肉干细胞身份背后的网络 - 重新提交 - 1
- 批准号:
10627924 - 财政年份:2021
- 资助金额:
$ 9.37万 - 项目类别:
Restoring ciliogenesis as a novel approach to blocking breast cancer growth
恢复纤毛发生作为阻止乳腺癌生长的新方法
- 批准号:
9292934 - 财政年份:2017
- 资助金额:
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Regulation of myogenic transcription by the Paf1C complex
Paf1C 复合物对肌源性转录的调节
- 批准号:
9537650 - 财政年份:2017
- 资助金额:
$ 9.37万 - 项目类别:
Epigenomic regulation in skeletal muscle cells and their precursors
骨骼肌细胞及其前体细胞的表观基因组调控
- 批准号:
9174484 - 财政年份:2016
- 资助金额:
$ 9.37万 - 项目类别:
The Role of pRB and Co-repressors in Transcriptional Regulation
pRB 和辅阻遏物在转录调控中的作用
- 批准号:
8764196 - 财政年份:2013
- 资助金额:
$ 9.37万 - 项目类别:
The Role of pRB and Co-repressors in Transcriptional Regulation
pRB 和辅阻遏物在转录调控中的作用
- 批准号:
8761281 - 财政年份:2013
- 资助金额:
$ 9.37万 - 项目类别:
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