Multidimensional <scp>OMICs</scp> reveal <scp>ARID1A</scp> orchestrated control of <scp>DNA</scp> damage, splicing, and cell cycle in normal‐like and malignant urothelial cells

Epigenetic regulators, such as the SWI/SNF complex, with important roles in tissue development and homeostasis, are frequently mutated in cancer. ARID1A, a subunit of the SWI/SNF complex, is mutated in approximately 20% of all bladder tumors; however, the consequences of this remain poorly understood. Finding truncations to be the most common mutation, we generated loss- and gain-of-function models to conduct RNA-Seq, interactome analyses, Omni-ATAC-Seq, and functional studies to characterize ARID1A-affected pathways potentially suitable for the treatment of ARID1A-deficient bladder cancers. We observed decreased cell proliferation and deregulation of stress-regulated pathways, including DNA repair, in ARID1A-deficient cells. Furthermore, ARID1A was linked to alternative splicing and translational regulation on RNA and interactome levels. ARID1A deficiency drastically reduced the accessibility of chromatin, especially around introns and distal enhancers, in a functional enrichment analysis. Less accessible chromatin areas were mapped to pathways such as cell proliferation and DNA damage response. Indeed, the G2/M checkpoint appeared impaired after DNA damage in ARID1A-deficient cells. Together, our data highlight the broad impact of ARID1A loss and the possibility of targeting proliferative and DNA repair pathways for treatment.