title: 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 squamous-like 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.
authors.affiliation: Department of Urology and Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Chunming
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Urology and Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Zarine R
authors.initials: ZR
authors.lastname: Balsara
authors.affiliation: Laboratory of Voiding Dysfunction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Warren G
authors.identifier: 0000-0002-2772-7264
authors.initials: WG
authors.lastname: Hill
authors.affiliation: Department of Urology and Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA sean.li@childrens.harvard.edu.
authors.forename: Xue
authors.identifier: 0000-0002-3072-0573
authors.initials: X
authors.lastname: Li
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D021122:Protein Subunits; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D001743:Urinary Bladder / Q000196:embryology / Q000254:growth & development* / Q000502:physiology*; D019459:Urothelium / Q000196:embryology / Q000254:growth & development* / Q000502:physiology*
chemical_list: C107275:Eed protein, mouse; D053823:Hedgehog Proteins; D021122:Protein Subunits; C465570:Shh protein, mouse; D063151:Polycomb Repressive Complex 2
keywords: Bladder; Eed; Epigenetics; Ezh2; Injury; Krt14; Krt17; Krt5; Mouse; PRC2; Regeneration; Shh; Squamous differentiation; Urothelium