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

Tavares, Manuel; Khandelwal, Garima; Muter, Joanne; Viiri, Keijo; Beltran, Manuel; Brosens, Jan J; Jenner, Richard G; (2022) JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation. Cell Reports , 39 (9) , Article 110889. 10.1016/j.celrep.2022.110889. Green open access

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Abstract

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.

Type: Article
Title: JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2022.110889
Publisher version: https://doi.org/10.1016/j.celrep.2022.110889
Language: English
Additional information: ©2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10149916
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