Chromatin dynamics, transcriptional activators and repressors in transition from proliferating progenitors to terminal differentiation during adult stem cell differentiation

成体干细胞分化过程中从增殖祖细胞向终末分化转变的染色质动力学、转录激活子和阻遏子

• 批准号: 9049981
• 负责人: Dan Lu
• 金额: $ 5.43万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049981
• 关键词: Binding; Binding Sites; Bioinformatics; Biological Assay; Biological Models; Cell Differentiation process; Cell Lineage; Cells; ChIP-seq; Chromatin; Complex; Data; Defect; Disease; Drosophila genus; Embryo; Ensure; Foundations; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genomics; Germ Cells; Germ Lines; Homeostasis; Lead; Life; Light; Male Infertility; Malignant Neoplasms; Maps; Meiosis; Methods; Modeling; NuRD complex; Polymerase; Population; Process; Proliferating; Promoter Regions; RNA Interference; RNA Polymerase II; Regenerative Medicine; Regulation; Repression; Resolution; Role; Somatic Cell; Spermatocytes; Spermatogenesis; Spermatogonia; Stem cells; TATA-Binding Protein Associated Factors; Testing; Testis; Therapeutic; Tissue Differentiation; Tissue-Specific Gene Expression; Tissues; To specify; Transcript; Transcription Coactivator; Transcription Initiation Site; Transcription Repressor/Corepressor; Transcriptional Activation; Transposase; adult stem cell; cell type; chromatin remodeling; in vivo; injured; insight; knock-down; male; prevent; progenitor; programs; promoter; public health relevance; repaired; stem cell differentiation; tissue repair; transcription factor; tumorigenesis

 DESCRIPTION (provided by applicant): Proper differentiation of adult stem cells is crucial for maintaining tissue homeostasis, repairing tissue damage, and preventing oncogenesis. During adult stem cell differentiation, the transition from proliferation to terminal differentiation is akey step because it makes an irreversible commitment toward terminal cell fate and is marked by dramatic changes in gene expression. The proposed project uses the process of germ line stem cell differentiation in male Drosophila as a model system to investigate the key mechanisms that regulate the stepwise changes in chromatin and transcription that drive the transition from proliferating spermatogonia to terminal differentiation in spermatocytes. The project aims to understand how chromatin dynamics, cell- type specific master transcriptional activators tTAFs and tMAC, and a newly discovered transcriptional repressor tZnF act together to turn on the correct transcription program for terminal differentiation. Specifically, the proposed project will investigate whether and how the change in expression of terminal differentiation genes during this transition is accompanied by dynamic changes in compaction of chromatin regions and recruitment of stalled RNA polymerase II preceding transcription. The chromatin dynamic data will also facilitate the search for transcription factors that regulate the expression of genes tha encode the master regulators tTAFs, tMAC components and tZnF. Lastly, hypotheses will be tested to understand how tZnF selectively inhibits a sub group of tMAC-dependent target genes to enforce lineage-specific gene expression. These results will provide a more detailed picture of the transition from proliferation to terminal differentiation, and provide insights on how key regulatory components collaborate to achieve proper initiation of terminal differentiation in adult stem cell lineages.

 描述(申请人提供)：成体干细胞的正确分化对于维持组织内环境稳定、修复组织损伤和防止肿瘤发生至关重要。在成体干细胞分化过程中，从增殖到终末分化的转变是一个关键步骤，因为它对终末细胞的命运做出了不可逆转的承诺，并以基因表达的剧烈变化为标志。该项目以雄性果蝇生殖系干细胞分化过程为模型系统，研究精母细胞从增殖的精原细胞向终末分化转变过程中，染色质和转录的逐步变化调控的关键机制。该项目旨在了解染色质动力学、细胞类型特异性主转录激活因子tTAFs和TMAC以及新发现的转录抑制因子tZnF是如何共同作用来启动正确的转录程序进行末端分化的。具体而言，拟议的项目将 研究在这一转变过程中，末端分化基因表达的变化是否以及如何伴随着染色质区域紧凑的动态变化和转录前停滞的RNA聚合酶II的招募。染色质的动态数据也将有助于寻找调控基因表达的转录因子，这些转录因子编码主要调节因子tTAFs、TMAC成分和tZnF。最后，将对假设进行检验，以了解tZnF如何选择性地抑制TMAC依赖的靶基因的子组，以加强谱系特异性基因的表达。这些结果将提供从增殖到终末分化的更详细的图景，并为关键调控成分如何协作以实现成人终末分化的适当启动提供洞察。 干细胞谱系。