BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation

Nat Commun. 2019 Jan 21;10(1):348. doi: 10.1038/s41467-018-08255-x.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism*
  • CRISPR-Cas Systems
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Drosophila melanogaster
  • Gene Editing
  • Haploidy
  • HeLa Cells
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism
  • Protein Processing, Post-Translational*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Sf9 Cells
  • Spodoptera
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitination

Substances

  • ASXL1 protein, human
  • ASXL2 protein, human
  • ASXL3 protein, human
  • BAP1 protein, human
  • Cell Cycle Proteins
  • Histones
  • PRC1 protein, human
  • Repressor Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Polycomb Repressive Complex 1
  • Ubiquitin Thiolesterase