Molecular mechanisms and (patho)physiological consequences of PRC2.1-mediated gene regulation

PRC2.1介导的基因调控的分子机制和（病理）生理后果

• 批准号: 384027541
• 负责人: Dr. Robert Liefke
• 金额: --
• 依托单位: Institut für Molekularbiologie und Tumorforschung (IMT)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/384027541?language=en
• 关键词: Molecular; mechanisms; patho; physiological; consequences

The Polycomb Repressive Complex 2 (PRC2) plays pivotal roles in several biological processes including embyrogenesis and cellular differentiation. It is composed of multiple subunits and serves to deposit the repressive H3K27me3 histone mark. Recent results show the existence of differentially composed PRC2 subcomplexes, such as the PRC2.1 subcomplex, which is characterized by the presence of the polycomb-like proteins (Pcl), EPOP (also known as C17orf96), but also by the absence of the JARID2 subunit . The Pcl proteins (PHF1, MTF2, PHF19) interact with the active histone mark H3K36me3 and unmethylated CpG islands, while EPOP associates with the transcription elongation factor Elongin BC and the deubiquitinase USP7. These interactions suggest a role for PRC2.1 during active gene transcription. So far, this aspect of Polycomb biology is only scarcely studied.Here I suggest a bipartite work program that studies in the first part the molecular mechanisms of gene regulation mediated by EPOP, which I have characterized during my postdoctoral work (Liefke et al., 2016; Liefke et al., 2015). I want to unravel the regulatory mechanisms of EPOP within the PRC2.1-complex, the importance of its interaction with Elongin BC and USP7, as well as the relevance of its posttranslational modifications. The second part addresses the functional role of PRC2.1 complex members in early mouse embryogenesis, in somatic reprogramming and in lung cancer. The function of EPOP for the establishment of the pluripotent epiblast (EPI) in early mouse embryos is studied using gain- and loss-of function approaches. The role of EPOP and its subdomains will be dissected during somatic reprogramming from mouse embryonic fibroblasts (MEFs). As the frequently observed upregulation of EPOP and the short isoform of PHF19 in human cancers coincides with a poor survival, we will study their contribution to oncogenic rewiring of signaling pathways and transcription programs taking lung cancer cells as our model system.The successful execution of this project would significantly expand our understanding of the regulatory role of PRC2.1 and its subunits and may lead to the discovery of strategies for therapeutic intervention.

多梳抑制复合物2（PRC 2）在胚胎发生和细胞分化等生物学过程中起着关键作用。它由多个亚基组成，用于存款抑制性H3 K27 me 3组蛋白标记。最近的结果表明存在差异组成的PRC 2亚复合物，如PRC2.1亚复合物，其特征在于存在多梳样蛋白（Pcl），EPOP（也称为C17 orf 96），但也不存在JARID 2亚基。Pcl蛋白（PHF 1、MTF 2、PHF 19）与活性组蛋白标记H3 K36 me 3和未甲基化的CpG岛相互作用，而EPOP与转录延伸因子Elongin BC和去泛素化酶USP 7相关联。这些相互作用表明PRC2.1在活跃的基因转录过程中的作用。到目前为止，Polycomb生物学的这一方面几乎没有研究。在这里，我建议一个两部分的工作计划，在第一部分研究由EPOP介导的基因调控的分子机制，我在博士后工作中描述了这一点（Liefke等人，2016; Liefke等人，2015年）的报告。我想解开PRC2.1复合物中EPOP的调控机制，它与Elongin BC和USP 7相互作用的重要性，以及它的翻译后修饰的相关性。第二部分讨论PRC2.1复合体成员在小鼠早期胚胎发生、体细胞重编程和肺癌中的功能作用。采用功能获得和功能丧失方法研究了EPOP在小鼠早期胚胎多能外胚层（EPI）建立中的功能。EPOP及其亚结构域的作用将在小鼠胚胎成纤维细胞（MEFs）的体细胞重编程过程中进行解剖。由于在人类癌症中经常观察到的EPOP和PHF 19的短同种型的上调与较差的存活率相一致，我们将以肺癌细胞为模型系统，研究它们对致癌信号通路和转录程序重新布线的贡献。该项目的成功执行将显著扩展我们对PRC2.1及其亚基调控作用的理解，并可能导致发现治疗干预的策略。