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

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27me3) to maintain gene repression and is essential for 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 abrogates interaction with specific PRC2 accessory factors, reduces occupancy at PRC2 target genes, and diminishes H3K27me3. Fusion to JAZF1 increases H4Kac at PRC2 target genes and triggers 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. These results reveal defects in chromatin regulation, gene expression, and cell differentiation caused by JAZF1-SUZ12 that may underlie its role in oncogenesis. [Display omitted] • JAZF1-SUZ12 fails to bind PRC2 subunits due to loss of the SUZ12 N terminus • JAZF1-SUZ12 switches to a JAZF1-like binding profile during cell differentiation • JAZF1-SUZ12 reduces H3K27me3 and increases H4Kac at polycomb target genes • JAZF1-SUZ12 activates polycomb target genes and dysregulates hEnSC decidualization Fusion of JAZF to SUZ12 often occurs in endometrial stromal sarcoma, but the effects of JAZF1-SUZ12 on chromatin and cell differentiation are not understood. Tavares et al. demonstrate that JAZF1-SUZ12 alters PRC2 composition and genome occupancy, reduces H3K27me3 and increases H4Kac, and dysregulates gene expression and endometrial stromal cell decidualization. [ABSTRACT FROM AUTHOR]