PT  - JOURNAL ARTICLE
AU  - Manuel Tavares
AU  - Garima Khandelwal
AU  - Joanne Mutter
AU  - Keijo Viiri
AU  - Manuel Beltran
AU  - Jan J. Brosens
AU  - Richard G. Jenner
TI  - JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation
AID  - 10.1101/2021.04.15.440052
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.15.440052
4099  - http://biorxiv.org/content/early/2021/04/15/2021.04.15.440052.short
4100  - http://biorxiv.org/content/early/2021/04/15/2021.04.15.440052.full
AB  - Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27me3) to maintain repression of genes specific for other cell types and is essential for cell differentiation. In endometrial stromal sarcoma, the PRC2 subunit SUZ12 is often fused with the NuA4/TIP60 subunit JAZF1. Here, we show that JAZF1-SUZ12 dysregulates PRC2 composition, recruitment, histone modification, gene expression and cell differentiation. The loss of the SUZ12 N-terminus in the fusion protein disrupted interaction with the PRC2 accessory factors JARID2, EPOP and PALI1 and prevented recruitment of PRC2 from RNA to chromatin. In undifferentiated cells, JAZF1-SUZ12 occupied PRC2 target genes but gained a JAZF1-like binding profile during cell differentiation. JAZF1-SUZ12 reduced H3K27me3 and increased H4Kac at PRC2 target genes, and this was associated with disruption in gene expression and cell differentiation programs. These results reveal the defects in chromatin regulation caused by JAZF1-SUZ12, which may underlie its role in oncogenesis.Competing Interest StatementThe authors have declared no competing interest.