GSE120302
Bap1 and RNF2 ChIP-seq in mES cells
Malignancies arising from mutation of tumor suppressor genes display an unexplained tissue  proclivity. For example, tumor suppressor BAP1 encodes a ubiquitously expressed deubiquitinase  for histone H2A but germline mutations predominantly cause uveal melanomas and  mesotheliomas. We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells,  fibroblasts, liver and pancreas, whereas melanocytes and mesothelial cells remain viable. E3 ligase  RNF2, which silences genes by monoubiquitinating H2A, promoted apoptosis in BAP1-deficient  cells by suppressing the pro-survival genes Bcl-2 and Mcl-1. Our data argue that BAP1 modulates  gene expression by countering H2A ubiquitination, but its loss only promotes tumorigenesis in  cells that do not engage an RNF2-dependent apoptotic program. We propose that intolerance of  BAP1 loss, and perhaps the loss of other tumor suppressors, restricts the mutant tumor spectrum. Overall design: ChIP-seq was performed on the following genotypes: BAP1-C91A mutant, BAP1-FLAG tag, BAP1 ChIP in BAP1 knock out, RNF2 wildtype, RNF2 ChIP in RNF2 knock out background, and RNF2 ChIP in BAP1 knock out background. Each experiement includes a corresponding input sample.