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ELUCIDATING THE FUNCTION OF THE POLYCOMB REPRESSIVE COMPLEX 2
EPIGENETIC PROGRAM IN BLADDER DEVELOPMENT AND REGENERATION
Zarine BALSARA, Chunming GUO and Sean LI
Boston Children's Hospital, Urology, Boston, USA
PURPOSE
The polycomb repressive complex 2 (PRC2) functions as an epigenetic modifier. Through trimethylation of lysine 27 on
histone H3 (H3K27me3), PRC2 represses gene expression. While PRC2 is critical in development and tissue
homeostasis, no studies have examined its role in the bladder. The aim of this study was to determine if PRC2 functions
in urothelial development and regeneration and repair.
MATERIAL AND METHODS
Using a conditional knock-out strategy, we generated mice in which Eed, the main structural component of PRC2, was
deleted in bladder urothelium. Urothelial development, differentiation, and regeneration were assessed through
immunohistochemical and immunofluorescence analyses and RT-PCR analysis.
RESULTS
H3K27 trimethylation is highly enriched in wild-type bladder urothelium compared to smooth muscle cells. Conditional
deletion of Eed leads to loss of H3K27me3 marks in bladder urothelium. This results in aberrant urothelial differentiation
characterized by premature differentiation of CK5+ basal cells and reduced numbers of p63+CK5- intermediate cells.
Likewise, loss of Eed leads to impaired proliferation of urothelial cells, which correlates with increased expression of the
cell cycle inhibitor p16. Loss of PRC2 activity also causes dysregulation of sonic hedgehog (Shh) signaling, a master
regulator of bladder development. Studies are underway to evaluate whether loss of Eed impairs urothelial regeneration
following chemical injury with cyclophosphamide or urinary tract infection.
CONCLUSIONS
PRC2 temporally regulates urothelial differentiation and proliferation during embryogenesis, partly through its actions on
Shh signaling and p16 expression. The role of PRC2 in homeostasis and regeneration of adult urothelium is actively
being investigated. These results indicate that urothelial development and differentiation is under epigenetic control.