Targeting the PRC2-dependent epigenetic program alleviates urinary tract infections

Chunming Guo; Mingyi Zhao; Xinbing Sui; Zarine Balsara; Songhui Zhai; Michael Ahdoot; Yingsheng Zhang; Christa M Lam; Ping Zhu; Xue Li

doi:10.1016/j.isci.2023.106925

Targeting the PRC2-dependent epigenetic program alleviates urinary tract infections

iScience. 2023 May 20;26(6):106925. doi: 10.1016/j.isci.2023.106925. eCollection 2023 Jun 16.

Authors

Chunming Guo^{1

2}, Mingyi Zhao^{2

3}, Xinbing Sui², Zarine Balsara², Songhui Zhai², Michael Ahdoot⁴, Yingsheng Zhang¹, Christa M Lam^{1

2}, Ping Zhu³, Xue Li^{1

2}

Affiliations

¹ 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.
² Departments of Urology and Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
³ 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.
⁴ Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis 3089, Los Angeles, CA 90048, USA.

Abstract

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.

Keywords: Epigenetics; Health sciences; Immunology; Molecular mechanism of gene regulation.

Abstract

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