Deciphering the epigenetic interplay to safeguard embryonic stem cell identity
From yeast to human, genomic DNA is tightly wrapped around nucleosomes forming a nucleo-protein complex called chromatin. Since chromatin packaging interferes with all DNA-templated events, regulation of gene expression involves chromatin modifying machines that can mobilize nucleosomes to increase or reduce DNA accessibility. Polycomb Repressive Complexes 1 (PRC1) and PRC2 are large multi-subunit complexes that modify chromatin structure to achieve transcriptional silencing of key developmental and signaling genes. Chromatin modifications include chemical modifications on nucleosomes, so-called epigenetic marks, that can promote inheritance of the repressive chromatin structure through cell divisions. Consistent with their critical function in controlling epigenetic silencing of key developmental genes, dysregulation of PRC1 or PRC2 is associated with a wide spectrum of diseases, including cancer. In mammals, PRC1 and PRC2 have radiated into large families of heterogenous multimeric complexes with divergent catalytic and non-catalytic functions. The roles of these different PRCs in development has been largely unclear.
The team around Oliver Bell at IMBA employed chemical genetics and epigenome profiling to gain new insights into the complex between canonical and variant PRC1 and PRC2 controlling mouse embryonic stem cell (mESC) identity. In the current publication, Oliver Bell and his group show that different PRC1 complexes and PRC2 act independently to maintain of repressive chromatin modifications and silence target genes. Individual loss of one pathway does not impair mESC self-renewal capacity. However, loss of both pathways leads to mESC differentiation and activation of a subset of developmental genes. Thus, parallel pathways explain the differential requirements for PRC1 and PRC2 and provide robust silencing of lineage-specific genes. “While this `double safety net` ensures that timing of lineage-specific gene activation is tightly controlled, redundancy presented a real barrier to dissect the mammalian Polycomb pathway genetically. Based on our new findings, we can take advantage of synthetic lethality screens to identify novel regulators of Polycomb activity“, says Oliver Bell, former group leader at IMBA, who now is Assistant Professor of Biochemistry and Molecular Medicine at the Keck School of Medicine of the University of Southern California in Los Angeles. This research was carried out at IMBA and offers new applications for in-vivo validation of Polycomb Repressive Complex inhibitors identified via the highly sensitive Polycomb screening tool that is available for industrial partnerships.
"Parallel PRC2/cPRC1 and vPRC1 pathways silence lineage-specific genes and maintain self-renewal in mouse embryonic stem cells", Zepeda-Martinez et al., Science Advances, 2020 doi:10.1126/sciadv.aax5692
IMBA - Institute of Molecular Biotechnology - is one of the leading biomedical research institutes in Europe focusing on cutting-edge stem cell technologies, functional genomics, and RNA biology. IMBA is located at the Vienna BioCenter, the vibrant cluster of universities, research institutes and biotech companies in Austria. IMBA is a subsidiary of the Austrian Academy of Sciences, the leading national sponsor of non-university academic research. The stem cell and organoid research at IMBA is being funded by the Austrian Federal Ministry of Science and the City of Vienna.