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.
Antoine Campagne  1  2 ,  Ming-Kang Lee  1  2 ,  Dina Zielinski  1  2  3 ,  Audrey Michaud  1  2 ,  Stéphanie Le Corre  1  2 ,  Florent Dingli  1 ,  Hong Chen  1  2 ,  Lara Z Shahidian  4 ,  Ivaylo Vassilev  1  2  3 ,  Nicolas Servant  1  3 ,  Damarys Loew  1 ,  Eric Pasmant  5 ,  Sophie Postel-Vinay  6 ,  Michel Wassef  7  8 ,  Raphaël Margueron  9  10
Affiliations
  • 1. Institut Curie, Paris Sciences et Lettres Research University, Sorbonne University, 75005, Paris, France.
  • 2. INSERM U934/CNRS UMR3215, 75005, Paris, France.
  • 3. INSERM U900, Mines ParisTech, 75005, Paris, France.
  • 4. Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, 85764, Germany.
  • 5. Department of Molecular Genetics Pathology, Cochin Hospital, HUPC AP-HP, EA7331, Faculty of Pharmacy, University of Paris Descartes, Paris, 75014, France.
  • 6. Département d'Innovation Thérapeutique et Essais Précoces, INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.
  • 7. Institut Curie, Paris Sciences et Lettres Research University, Sorbonne University, 75005, Paris, France. [email protected].
  • 8. INSERM U934/CNRS UMR3215, 75005, Paris, France. [email protected].
  • 9. Institut Curie, Paris Sciences et Lettres Research University, Sorbonne University, 75005, Paris, France. [email protected].
  • 10. INSERM U934/CNRS UMR3215, 75005, Paris, France. [email protected].
PMID: 30664650 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.