Stage- and subunit-specific functions of polycomb repressive complex 2 in bladder urothelial formation and regeneration

Abstract

Urothelium is the protective lining of the urinary tract. The mechanisms underlying urothelial formation and maintenance are largely unknown. Here, we report the stage-specific roles of PRC2 epigenetic regulators in embryonic and adult urothelial progenitors. Without Eed, the obligatory subunit of PRC2, embryonic urothelial progenitors demonstrate reduced proliferation with concomitant dysregulation of genes including Cdkn2a ( p16), Cdkn2b ( p15) and Shh. These mutants display premature differentiation of keratin 5-positive (Krt5 + ) basal cells and ectopic expression of squamouslike differentiation markers. Deletion of Ezh2, the major enzymatic component of PRC2, causes upregulation of Upk3a + superficial cells. Unexpectedly, Eed and Eed/Ezh2 double mutants exhibit delayed superficial cell differentiation. Furthermore, Eed regulates the proliferative and regenerative capacity of adult urothelial progenitors and prevents precocious differentiation. Collectively, these findings uncover the epigenetic mechanism by which PRC2 controls urothelial progenitor cell fate and the timing of differentiation, and further suggest an epigenetic basis of urothelial maintenance and regeneration.

X chromosome protects against bladder cancer in females via aKDM6A-dependent epigenetic mechanism

“…To determine whether Kdm6a functions as a tumor suppressor in vivo, we crossed mice with a conditional allele of Kdm6a ( 24 ) with a urothelium-specific Cre driver, Upk2-Cre ( 26 ). The resulting Kdm6a conditional knockout (cKO) mice were viable and fertile with no apparent phenotype.…”

“…Eed is an obligatory component of PRC2. We have reported that urothelium-specific cKO of Eed completely abolishes PRC2 activity ( 26 ). We found that Cdkn1a was significantly up-regulated in the bladder urothelium of Eed cKO mice ( Fig.…”

“…Mating of XYM mice with wild-type C57Bl/6J female (XXF) mice generated an offspring with one of the four genotypes, including XXF, XXM, XYF, and XYM. The Eed conditional allele and Upk2-Cre transgenic line were reported previously ( 26 ). All mice were maintained on a C57Bl/6J background.…”

The PRC2-dependent epigenetic reprograming of the bladder epithelium exacerbates urinary tract infections

“…Intriguingly, exposure of human bladder urothelial carcinoma cells to UPEC in vitro induces expression of Ezh2, the methyltransferase of polycomb repressor complex 2 (PRC2) (43), which catalyzes formation of H3K27me3. We have previously reported that the PRC2-dependent H3K27me3 modification plays a critical role in the bladder urothelium during embryonic development (9). However, it's potential role in mature urothelial cells during UTIs has not been reported yet.…”

“…Nevertheless, bladder urothelium has a remarkable regenerative capacity to maintain its barrier function after injuries (8). For example, during urinary tract infections (UTIs), the quiescent urothelium becomes hyperproliferative and regenerates the superficial or umbrella cells within days to repair the damaged tissue (9)(10)(11)(12)(13). The rapid regenerative kinetics of the bladder urothelium appears to be biologically necessary for the restoration of the barrier function.…”