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 sub...

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Bibliographic Details
Published in:Developmental biology 2022-05, Vol.485, p.61-69
Main Authors: Guo, Chunming, Zhang, Yingsheng, Tan, Ruirong, Tang, Zonghao, Lam, Christa M., Ye, Xing, Wang, Zhong, Li, Xue
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - genetics
Animals
ARID1A
Bladder
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Epigenesis, Genetic
Epigenetics
Mice
Mice, Knockout
Polycomb Repressive Complex 2 - metabolism
PRC2
Regeneration
SWI/SNF
Transcription Factors - genetics
Transcription Factors - metabolism
Urinary Bladder - metabolism
Urothelium
Urothelium - metabolism
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Summary: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. [Display omitted] •Loss-of-Arid1a causes hyperproliferation of bladder urothelial cells.•Arid1a antagonizes the Ezh2 epigenetic program during urothelium development.•Arid1a plays distinct roles in the development and regeneration of the urothelium.
ISSN:0012-1606
1095-564X
DOI:10.1016/j.ydbio.2022.02.008