Targeting the PRC2-dependent epigenetic program alleviates urinary tract infections.
Targeting the PRC2-dependent epigenetic program alleviates urinary tract infections.
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DOI：
10.1016/j.isci.2023.106925
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发表时间：
2023-06-16
期刊：
影响因子：
5.8
通讯作者：
Li, Xue
中科院分区：
文献类型：
--
作者：
Guo, Chunmin;Zhao, Mingy;Sui, Xinbin;Balsara, Zarin;Zhai, Songhui;Ahdoot, Michael;Zhang, Yingshen;Lam, Christa M.;Zhu, Ping;Li, Xue
尿路感染（UTI）是世界范围内普遍存在的健康问题。有尿路感染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，我们发现膀胱感染诱导膀胱尿路上皮细胞表达Ezh2。Ezh2是多梳抑制复合物2 （PRC2）的甲基转移酶，是一种有效的表观遗传调节剂。尿路盐特异性PRC2失活导致尿细菌负荷减少，炎症反应减弱，NF-κB信号通路活性降低。PRC2失活还通过减少基底细胞增生和增加尿路上皮分化，促进尿路感染引起的尿路上皮损伤后的适当再生。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预后。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幅度和uti的严重程度，Ezh2抑制剂可能是治疗慢性和严重uti的一种可行的非抗生素策略。尿路感染诱导膀胱表观遗传重构，重构加剧炎症宿主对随后感染的反应。靶向prc2依赖性表观遗传程序减少炎症损伤Ezh2抑制剂治疗性地减轻小鼠模型中的尿路感染基因调控的分子机制；表观遗传学;免疫学
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. UTI induces epigenetic remodeling of the bladder The remodeling exacerbates inflammatory host response to subsequent infections Targeting the PRC2-dependent epigenetic program reduces inflammatory damage Ezh2 inhibitors therapeutically alleviate UTIs in mouse models Health sciences; Molecular mechanism of gene regulation; Epigenetics; Immunology
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影响因子：
4.5
作者：
Iannetti A;Ledoux AC;Tudhope SJ;Sellier H;Zhao B;Mowla S;Moore A;Hummerich H;Gewurz BE;Cockell SJ;Jat PS;Willmore E;Perkins ND
通讯作者：
Perkins ND
DOI：
10.1038/nrmicro3432
发表时间：
2015-05
期刊：
Nature reviews. Microbiology
影响因子：
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影响因子：
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影响因子：
16
作者：
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影响因子：
3.1
作者：
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通讯作者：
Schaeffer, AJ