Abstract
In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing. The mammalian homologs of these proteins (BAP1 and ASXL1/2/3, respectively), are frequently mutated in various cancer types, yet their precise functions remain unclear. Using an integrative approach based on isogenic cell lines generated with CRISPR/Cas9, we uncover an unanticipated role for BAP1 in gene activation. This function requires the assembly of an enzymatically active BAP1-associated core complex (BAP1.com) containing one of the redundant ASXL proteins. We investigate the mechanism underlying BAP1.com-mediated transcriptional regulation and show that it does not participate in Polycomb-mediated silencing. Instead, our results establish that the function of BAP1.com is to safeguard transcriptionally active genes against silencing by the Polycomb Repressive Complex 1.
Highlights
In Drosophila, a complex consisting of Calypso and Additional Sex Combs (ASX) catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing
In order to comprehend the role of BRCA1-associated protein 1 (BAP1) in transcriptional regulation, we generated knockouts (KOs) for BAP1, ASXL1, ASXL2, and EZH2, the main catalytic subunit of PRC2, in human HAP1 cells, a model cell line that is nearly haploid and amenable to genome editing[33]
We performed extensive biochemical and genetic analyses in isogenic mutant cell lines to address the role of BAP1 in transcriptional regulation, the respective contributions of BAP1 and the ASXL proteins to the regulation of gene expression and the interplay between BAP1.com and the Polycomb machinery
Summary
In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing. Using an integrative approach based on isogenic cell lines generated with CRISPR/Cas[9], we uncover an unanticipated role for BAP1 in gene activation This function requires the assembly of an enzymatically active BAP1-associated core complex (BAP1.com) containing one of the redundant ASXL proteins. Our results establish that the function of BAP1.com is to safeguard transcriptionally active genes against silencing by the Polycomb Repressive Complex 1. Some studies have reported that BAP1 acts as a transcriptional activator while others have suggested that it is required for gene silencing[3,4,12]. Our integrative analysis uncovers an essential function for BAP1.com as a transcriptional co-activator, acting by locally antagonizing PRC1 activity
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