Epigenetic memory of cell identity
Cell identity is determined by specific gene expression patterns that are typically inherited through genome replication and cell divisions to ensure the integrity of tissues and organs. As the DNA is tightly wrapped around nucleosomes, restricting access to the genetic information, transcription factors rely on nucleosome-modifying complexes to control gene expression. Alteration of nucleosomes, including chemical modifications, are thought to serve as epigenetic signals at genes promoting the inheritance of “ON” or “OFF” states.
Nucleosome-modifying complexes of the Polycomb group family play an important role in epigenetic silencing of key developmental genes. Aberrant regulation of Polycomb Repressive Complexes is frequently associated with disease, including cancers, underscoring their importance in epigenetic memory of cell identity. The underlying mechanisms of epigenetic inheritance are poorly understood, however. Oli Bell’s lab at IMBA has now published new evidence showing that Polycomb-mediated inheritance of gene silencing is sustained by chemical nucleosome modifications that promote a feedback loop between canonical Polycomb Repressive Complex 1 (PRC1) and PRC2.
“By recapitulating Polycomb-dependent nucleosome modifications and gene silencing in mouse embryonic stem cells, we have been able to dissect the mechanisms in vivo and identify the key protagonists of epigenetic regulation,” says Oli Bell.
Their findings, published in “Nature Communications” this week, provide entry points for the development of new therapies targeting aberrant Polycomb-dependent repression associated with different types of cancer, including Non-Hodgkin Lymphoma and paediatric cancers. By recapitulating Polycomb regulation with the Polycomb in vivo assay, the team developed a highly sensitive screening tool that may aid the identification of small molecules that target cancer driven by aberrant Polycomb activity.
Original Paper: Moussa & Bsteh et al. (2019). Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing. Nat Commun. 2019; 10: 1931 doi.org/10.1038/s41467-019-09628-6