The role of polycomb group proteins in haematopoietic stem cells
Polycomb group (PcG) proteins are epigenetic repressors that are frequently overexpressed or mutated in cancer. PcG proteins function as three distinct complexes: Polycomb Repressive Complex 1 (PRC1), PRC2 and PhoRC. These complexes have roles in proliferation, apoptosis, skeletal development and stem cell biology. The predominant model for PRC action suggests that the PRCs act sequentially to elicit gene silencing; PhoRC directs PRC2 via its sequence specificity, PRC1 is then recruited and mediates transcriptional repression. This hierarchical recruitment model for PRC action is based on evidence from Drosophila, and mammalian ES and fibroblast cell lines. However, it is becoming clear that this model does not always hold true. In haematopoietic stem cells, a clinically relevant cell type, we know that PRC1 acts to enhance HSC activity, while PRC2 acts to restrict activity. These apparently opposing roles suggest that the complexes do not work in unison in these primary stem cells, and there is now evidence to suggest that the relationship is also unclear in leukaemia and breast cancer. We are studing the interaction between the three complexes using key knockouts or knockdowns of each complex, their molecular roles in terms of chromatin structure and gene expression and their functional consequences on HSC activity.
In collaboration with Dr Ian Majewski, Netherlands Cancer Institute; Professor Warren Alexander, Cancer and Haematology division; Associate Professor Gordon Smyth, Dr Matthew Ritchie and Dr Alicia Oshlack, Bioinformatics division.