Targeting the PRC2-dependent epigenetic program alleviates urinary tract infections.

Autor:	Guo C; 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., Zhao M; Departments of Urology and Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.; Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Pathogenesis, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, Guangdong 510100, China., Sui X; Departments of Urology and Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA., Balsara Z; Departments of Urology and Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA., Zhai S; Departments of Urology and Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA., Ahdoot M; Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis 3089, Los Angeles, CA 90048, USA., Zhang Y; 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., Lam CM; 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., Zhu P; Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Pathogenesis, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, Guangdong 510100, China., Li X; 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.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2023 May 20; Vol. 26 (6), pp. 106925. Date of Electronic Publication: 2023 May 20 (Print Publication: 2023).
DOI:	10.1016/j.isci.2023.106925
Abstrakt:	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 Ezh2 in bladder urothelial cells. Ezh2 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 NF-κB 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. Competing Interests: The authors declare no competing interests. (© 2023 The Author(s).)
Databáze:	MEDLINE
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