UCL Cancer Institute



Epigenetic dysregulation in cancer

PRC2 function is often dysregulated in cancer, either due to gene deletion, gene overexpression, point mutations or gene fusion events. Around 50% of cases of low-grade endometrial stromal sarcoma exhibit fusion of the gene encoding the PRC2 subunit SUZ12 with the gene encoding the NuA4-associated protein JAZF1. We have discovered that this fusion protein lacks interaction with specific PRC2 accessory factors, alters PRC2 gene occupancy and histone modification, and disrupts gene expression and cell differentiation. We currently working to understand the role of enhancer RNAs in oncogene activation and whether G4 RNA can be used to evict PRC2 from tumour-suppressor genes.

Loss of the SUZ12 N terminus prevents interaction of JAZF1-SUZ12 with EPOP, PALI1, and JARID2, decreasing PRC2 occupancy and reducing H3K27me3 at polycomb target genes. Fusion to JAZF1 induces association with NuA4/TIP60 and increases H4Kac at these sites. These changes are mirrored by ectopic activation of polycomb target genes in hEnSCs, inducing part of the decidualization gene expression program that lacks activation of immune response genes associated with clearance of senescent decidual cells from the endometrium