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: 9208056
• 负责人: Dan Lu
• 金额: $ 5.71万
• 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/9208056
• 关键词: Alpha Cell; Binding; Binding Sites; Bioinformatics; Biological Assay; Biological Models; Cell Differentiation process; Cell Lineage; Cells; ChIP-seq; Chromatin; Complex; DNA Polymerase II; DNA-Directed RNA Polymerase; Data; Defect; Differentiated Gene; Disease; Dreams; 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; Population; Process; Proliferating; Promoter Regions; RNA Interference; Recruitment Activity; Regenerative Medicine; Regulation; Repression; Resolution; Role; Somatic Cell; Spermatocytes; Spermatogenesis; Spermatogonia; Stem cells; TATA-Binding Protein Associated Factors; Testing; Testis; Therapeutic; Tissue-Specific Gene Expression; Tissues; To specify; Transcript; Transcription Coactivator; Transcription Initiation Site; Transcription Repressor/Corepressor; Transcriptional Activation; Transposase; adult stem cell; cell type; 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.