BET regulation of mitosis and pluripotency establishment
有丝分裂和多能性建立的 BET 调节
基本信息
- 批准号:10455668
- 负责人:
- 金额:$ 12.66万
- 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:2018-08-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAffinityBRD2 geneBindingBiochemical ProcessBioinformaticsBiologicalBiological AssayBiological ProcessBromodomainC-terminalCell CycleCell ProliferationCell physiologyCellsChIP-seqChemicalsChromatinDataDevelopmentDiabetes MellitusDiseaseDisease ManagementEpilepsyExcisionFibroblastsFunctional disorderGenetic TranscriptionGoalsHistonesHumanHuman ActivitiesIndividualInflammationInvestigationKnowledgeLaboratoriesLanguageLeadLigandsMalignant NeoplasmsMapsMasksMemoryMitosisMitoticMitotic ActivityModelingMolecularMutagenesisOutcomePeptidesPluripotent Stem CellsProtein IsoformsProteinsReaderReadingRegenerative MedicineRegulationReportingSignal TransductionTailTestingTestisVirus Replicationchemical bindingchemical functiondisorder controlhuman diseasehuman pluripotent stem cellinhibitorinnovationinsightmembermetaplastic cell transformationmolecular modelingnovelpluripotencyprotein protein interactionstem cellstranscriptome sequencing
项目摘要
Bromodomain extra terminal (BET) proteins are critical readers of the histone acetyl marks, which generally
signal active transcription. Human BET proteins include the ubiquitous BRD2, BRD3, and BRD4, as well as the
testis-specific BRDt. They are key regulators of mitosis and pluripotency reprogramming among many other
cellular and biological processes including transcription, cell cycle, transcriptional memory, and stem cell
identity, as well as viral replication and transcription. Bromodomains (BD) in BET proteins are the
acetyllysine(KAc)-binding modules capable of binding to acetylated core histones. BET proteins are
characterized by two tandem bromodomains (BD-I and BD-II) at their N-termini. Of note, the two tandem BDs
within each BET member are much more diverse than the equivalent BDs among BET member proteins. In
spite of intense investigation, many fundamental questions about these readers of chromatin acetyl marks
remain unsolved. Why are there two BDs within each BET protein? Why are the two tandem BDs of each BET
protein more diverse than the equivalent BDs among the BET member proteins? What are the specific acetyl
marks of histones each individual BD differentially recognizes? Does each individual BD specifically regulate
any biological process? Why do each of human BRD3 and BRD4 has both long and short isoforms? How is the
chromatin-reading activity of each BD regulated? As mitotic proteins, how is their mitotic activity tightly
controlled? Recent findings in my laboratory have paved an avenue to answering many, if not all, of these
fundamental questions. We recently reported that BRD3R, a truncated isoform of human BRD3, uniquely
enhances cellular pluripotency reprogramming via regulating mitosis. Our further preliminary data suggest that
these BRD3R activities are a result of unmasking of the chromatin-reading activities of the second
bromodomain (BD-II) of BRD3/BRD3R due to the absence of the long C-terminal tail. Our additional data
suggest that intramolecular masking of the BD-II activities may be a general mechanism among BET proteins.
We will study how intramolecular masking/unmasking regulate biological and chemical functions of the two
distinct BET bromodomains (Aims 1, 2, and 3). We will also identify the chromatin underpinnings behind the
different biological and cellular functions of the two distinct KAc-binding modules of BET proteins (Aim 3). To
achieve our goals, we will use up-to-date yet firmly established approaches including the chemically defined
reprogramming media, ChIP-seq, ChIP-qPCR, RNA-seq, bioinformatics, histone-tail-peptide pull-down,
histone-peptide array, ligand affinity assay, mutagenesis, protein-protein interaction, and others. Dysregulation
of the BET KAc-reading activities are implicated in various human diseases such as inflammation, diabetes, and
various cancers. The fundamental knowledge gained in this proposed study will provide a scientific basis for
the disease control and management for the BET-associated diseases.
溴结构域额外末端 (BET) 蛋白是组蛋白乙酰标记的关键读取者,通常
信号主动转录。人类 BET 蛋白包括普遍存在的 BRD2、BRD3 和 BRD4,以及
睾丸特异性 BRDt。它们是有丝分裂和多能性重编程等许多其他过程的关键调节因子
细胞和生物过程,包括转录、细胞周期、转录记忆和干细胞
身份,以及病毒复制和转录。 BET 蛋白中的溴结构域 (BD) 是
乙酰赖氨酸 (KAc) 结合模块能够结合乙酰化核心组蛋白。 BET 蛋白质是
其 N 末端有两个串联溴结构域(BD-I 和 BD-II)。值得注意的是,两个串联 BD
每个 BET 成员中的 BD 比 BET 成员蛋白中的同等 BD 更加多样化。在
尽管进行了深入的调查,但关于这些染色质乙酰标记读取器的许多基本问题
仍未解决。为什么每个 BET 蛋白中有两个 BD?为什么每个BET的两个串联BD
蛋白质比 BET 成员蛋白质中的同等 BD 更多样化?具体的乙酰基有哪些
每个 BD 差异识别的组蛋白标记?每个BD是否具体规定
任何生物过程?为什么人类 BRD3 和 BRD4 都有长亚型和短亚型?怎么样
每个 BD 的染色质读取活性受到调节吗?作为有丝分裂蛋白,它们的有丝分裂活性是如何紧密结合的
受控?我实验室的最新发现为回答其中许多(如果不是全部)问题铺平了道路
基本问题。我们最近报道了 BRD3R,人类 BRD3 的截短亚型,具有独特的
通过调节有丝分裂增强细胞多能性重编程。我们进一步的初步数据表明
这些 BRD3R 活性是第二个染色质读取活性被揭露的结果
BRD3/BRD3R 的溴结构域 (BD-II) 由于缺少长 C 末端尾部。我们的附加数据
表明 BD-II 活性的分子内掩蔽可能是 BET 蛋白的一般机制。
我们将研究分子内掩蔽/解掩蔽如何调节两者的生物和化学功能
不同的 BET 溴结构域(目标 1、2 和 3)。我们还将确定背后的染色质基础
BET 蛋白的两个不同的 KAc 结合模块的不同生物学和细胞功能(目标 3)。到
为了实现我们的目标,我们将使用最新但牢固确立的方法,包括化学定义的方法
重编程介质、ChIP-seq、ChIP-qPCR、RNA-seq、生物信息学、组蛋白尾肽下拉、
组蛋白-肽阵列、配体亲和力测定、诱变、蛋白质-蛋白质相互作用等。失调
BET KAc 读取活动与多种人类疾病有关,例如炎症、糖尿病和
各种癌症。这项拟议研究中获得的基础知识将为
BET 相关疾病的疾病控制和管理。
项目成果
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{{ truncateString('Kejin Hu', 18)}}的其他基金
BET regulation of mitosis and pluripotency establishment
有丝分裂和多能性建立的 BET 调节
- 批准号:
10225614 - 财政年份:2018
- 资助金额:
$ 12.66万 - 项目类别:
BET regulation of mitosis and pluripotency establishment
有丝分裂和多能性建立的 BET 调节
- 批准号:
9982351 - 财政年份:2018
- 资助金额:
$ 12.66万 - 项目类别:
BET Regulation of Mitosis and Pluripotency Establishment
有丝分裂和多能性建立的 BET 调节
- 批准号:
10829057 - 财政年份:2018
- 资助金额:
$ 12.66万 - 项目类别:
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