JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation

In low-grade endometrial stromal sarcoma (LG-ESS), the PRC2 subunit SUZ12 is often fused with the NuA4/TIP60 subunit JAZF1. We show that JAZF1-SUZ12 dysregulates PRC2 composition, genome occupancy, histone modification, gene expression and cell differentiation.

Loss of the SUZ12 N-terminus in the fusion protein abrogated interaction with specific PRC2 accessory factors, reduced occupancy at PRC2 target genes, and diminished H3K27me3. Fusion to JAZF1 increased H4Kac at PRC2 target genes and triggered recruitment to JAZF1 binding sites during cell differentiation. In human endometrial stromal cells, JAZF1-SUZ12 upregulated PRC2 target genes normally activated during decidualization while repressing genes associated with immune clearance, and JAZF1-SUZ12-induced genes were also overexpressed in LG-ESS.