SRA

Mutations in the BAF chromatin remodeling complex rank among the most frequent genetic alterations in human cancers, many of which result in a loss of function of the respective subunits. Recent genomic and chemical screens have revealed synthetic lethal interactions of BAF complex subunits with each other as well as with further chromatin modifiers. Using an epigenome-focused shRNA library, we identified loss of the histone chaperone complex CAF-1 (chromatin assembly factor 1) as a synthetic lethal vulnerability of ARID1A-deficient cells that is enhanced by the androgen receptor agonist testosterone. In line with antagonistic roles of the CAF-1 and BAF complexes in nucleosome deposition and remodeling, we show that knock-down of CAF-1 subunits results in a partial reversal of the transcriptional and chromatin accessibility effects caused by loss of ARID1A. Together, our findings identify a new functional partner of the BAF chromatin remodeling complex and represent a potential novel strategy for targeting ARID1A-deficient cancers. Overall design: 160 ATAC-seq samples for ARID1A knockout and WT HAP1 cells further perturbed with CHAF1A knockdown, degradation or EZH2 inhibitor or Testorsterone.