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

 描述（由申请人提供）：成体干细胞的适当分化对于维持组织稳态、修复组织损伤和预防肿瘤发生至关重要。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，因为它向终末细胞命运做出了不可逆的承诺，并以基因表达的显著变化为标志。该项目使用雄性果蝇生殖系干细胞分化过程作为模型系统，以研究调节染色质和转录逐步变化的关键机制，这些变化驱动着精原细胞从增殖到精母细胞终末分化的转变。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tTAF和tMAC以及一种新发现的转录抑制因子tZnF如何共同作用，以启动正确的转录程序进行终末分化。具体而言，拟议项目将 研究是否以及如何在这一转变过程中的终末分化基因的表达变化是伴随着动态变化的染色质区域的压实和招聘停滞RNA聚合酶II转录前。染色质动态数据也将有助于寻找调节基因表达的转录因子，这些基因编码主调节因子tTAF、tMAC组分和tZnF。最后，假设将进行测试，以了解tZnF如何选择性地抑制一个亚组的tMAC依赖性靶基因，以执行谱系特异性基因表达。这些结果将提供从增殖到终末分化的过渡的更详细的图片，并提供关于关键调控组分如何协作以实现成人终末分化的适当起始的见解。 干细胞谱系

 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.