Guo Chunming, Balsara Zarine R, Hill Warren G, Li Xue
Department of Urology and Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Laboratory of Voiding Dysfunction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Development. 2017 Feb 1;144(3):400-408. doi: 10.1242/dev.143958. Epub 2017 Jan 3.
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.
尿路上皮是尿路的保护性内衬。尿路上皮形成和维持的潜在机制在很大程度上尚不清楚。在此，我们报告了PRC2表观遗传调节因子在胚胎和成体尿路上皮祖细胞中的阶段特异性作用。没有PRC2的必需亚基Eed，胚胎尿路上皮祖细胞的增殖减少，同时包括Cdkn2a（p16）、Cdkn2b（p15）和Shh在内的基因表达失调。这些突变体表现出角蛋白5阳性（Krt5）基底细胞的过早分化以及鳞状样分化标志物的异位表达。PRC2的主要酶成分Ezh2的缺失导致Upk3a表层细胞上调。出乎意料的是，Eed和Eed/Ezh2双突变体表现出表层细胞分化延迟。此外，Eed调节成体尿路上皮祖细胞的增殖和再生能力，并防止过早分化。总的来说，这些发现揭示了PRC2控制尿路上皮祖细胞命运和分化时间的表观遗传机制，并进一步提示了尿路上皮维持和再生的表观遗传基础。
