Guo Chunming, Zhao Mingyi, Sui Xinbing, Balsara Zarine, Zhai Songhui, Ahdoot Michael, Zhang Yingsheng, Lam Christa M, Zhu Ping, Li Xue
Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis 3089, Los Angeles, CA 90048, USA.
Departments of Urology and Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
iScience. 2023 May 20;26(6):106925. doi: 10.1016/j.isci.2023.106925. eCollection 2023 Jun 16.
Urinary tract infection (UTI) is a pervasive health problem worldwide. Patients with a history of UTIs suffer increased risk of recurrent infections, a major risk of antibiotic resistance. Here, we show that bladder infections induce expression of in bladder urothelial cells. is the methyltransferase of polycomb repressor complex 2 (PRC2)-a potent epigenetic regulator. Urothelium-specific inactivation of PRC2 results in reduced urine bacterial burden, muted inflammatory response, and decreased activity of the signaling pathway. PRC2 inactivation also facilitates proper regeneration after urothelial damage from UTIs, by attenuating basal cell hyperplasia and increasing urothelial differentiation. In addition, treatment with Ezh2-specific small-molecule inhibitors improves outcomes of the chronic and severe bladder infections in mice. These findings collectively suggest that the PRC2-dependent epigenetic reprograming controls the amplitude of inflammation and severity of UTIs and that Ezh2 inhibitors may be a viable non-antibiotic strategy to manage chronic and severe UTIs.
尿路感染（UTI）是全球普遍存在的健康问题。有UTI病史的患者复发感染的风险增加，这是抗生素耐药性的主要风险。在这里，我们表明膀胱感染会诱导膀胱尿路上皮细胞中 的表达。 是多梳抑制复合物2（PRC2）的甲基转移酶——一种强大的表观遗传调节因子。PRC2在尿路上皮中的特异性失活导致尿液细菌负荷降低、炎症反应减弱以及 信号通路的活性降低。PRC2失活还通过减弱基底细胞增生和增加尿路上皮分化，促进UTI导致的尿路上皮损伤后的正常再生。此外，用Ezh2特异性小分子抑制剂治疗可改善小鼠慢性和严重膀胱感染的结果。这些发现共同表明，依赖PRC2的表观遗传重编程控制着炎症的程度和UTI的严重程度，并且Ezh2抑制剂可能是管理慢性和严重UTI的一种可行的非抗生素策略。
