Arid1a regulates bladder urothelium formation and maintenance.

Epigenetic regulation of gene expression plays a central role in bladder urothelium development and maintenance. ATPase-dependent chromatin remodeling is a major epigenetic regulatory mechanism, but its role in the bladder has not been explored.

Here, we show the functions of Arid1a, the largest subunit of the SWI/SNF or BAF chromatin remodeling ATPase complex, in embryonic and adult bladder urothelium. Knockout of Arid1a in urothelial progenitor cells significantly increases cell proliferation during bladder development. Deletion of Arid1a causes ectopic cell proliferation in the terminally differentiated superficial cells in adult mice. Consistently, gene-set enrichment analysis of differentially expressed genes demonstrates that the cell cycle-related pathways are significantly enriched in Arid1a knockouts. Gene-set of the polycomb repression complex 2 (PRC2) pathway is also enriched, suggesting that Arid1a antagonizes the PRC2-dependent epigenetic gene silencing program in the bladder. During acute cyclophosphamide-induced bladder injury, Arid1a knockouts develop hyperproliferative and hyperinflammatory phenotypes and exhibit a severe loss of urothelial cells. A Hallmark gene-set of the oxidative phosphorylation pathway is significantly reduced in Aria1a mutants before injury and is unexpectedly enriched during injury response. Together, this study uncovers functions of Arid1a in both bladder progenitor cells and the mature urothelium, suggesting its critical roles in urothelial development and regeneration.

Developmental biology. 2022 Mar 10 [Epub]

Chunming Guo, Yingsheng Zhang, Ruirong Tan, Zonghao Tang, Christa M Lam, Xing Ye, Zhong Wang, Xue Li

Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis 3089, Los Angeles, CA, 90048, USA., Department of Cardiac Surgery Cardiovascular Research Center, University of Michigan, Ann Arbor, MI, 48109, USA., Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis 3089, Los Angeles, CA, 90048, USA. Electronic address: .

Read an Expert Commentary by Bishoy Faltas, MD