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

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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.