{"title":"Targeting MLL1/WDR5-Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a","authors":"Daisuke Hara, Kensuke Sasaki, Shigehiro Doi, Takeshi Ike, Kazuya Maeda, Maria Yoshida, Akira Takahashi, Yosuke Osaki, Naoki Ishiuchi, Yujiro Maeoka, Toshiki Doi, Takuto Chiba, Ayumu Nakashima, Takao Masaki","doi":"10.1096/fj.202402382R","DOIUrl":null,"url":null,"abstract":"<p>Peritoneal fibrosis poses a significant challenge to the long-term efficacy of peritoneal dialysis (PD), with emerging evidence highlighting the role of cellular senescence in its pathogenesis. p16<sup>INK4a</sup> is a cell cycle regulator that has been implicated in cellular senescence. Mixed-lineage leukemia 1 (MLL1) forms a complex with WD-40 repeat protein 5 (WDR5) and exhibits histone H3K4 methyltransferase activity. We have previously shown that inhibition of the MLL1/WDR5 complex reduces p16<sup>INK4a</sup> expression and attenuates renal senescence after injury in mice. This study aimed to investigate whether inhibiting MLL1/WDR5 attenuates peritoneal senescence, inflammation, and fibrosis in both human samples and in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO-injected mice), while also exploring the associated underlying mechanisms. MLL1/WDR5, histone 3 lysine 4 trimethylation (H3K4me3), and p16<sup>INK4a</sup> expression were elevated in TGF-β1-stimulated human peritoneal mesothelial cells (HPMCs), non-adherent cells obtained from patients undergoing PD, and the submesothelial compact zones of MGO-injected mice. Notably, p16<sup>INK4a</sup> expression in these cells was positively correlated with the dialysate/plasma creatinine ratio. Treatment with the MLL1/WDR5 protein–protein interaction inhibitors MM-102 and OICR-9429 reduced H3K4me3 levels and p16<sup>INK4a</sup> expression, suppressing fibrosis in HPMCs as well as peritoneal fibrosis and inflammation in MGO-injected mice. These inhibitors also improved peritoneal function in MGO-injected mice. Additionally, we demonstrated that MLL1/WDR5-induced H3K4me3 directly regulates <i>p16</i><sup><i>INK4a</i></sup> gene transcription, and that inhibiting MLL1/WDR5 reduces H3K4me3, thereby suppressing <i>p16</i><sup><i>INK4a</i></sup> gene transcription. These findings suggest that targeting MLL1/WDR5 activation alleviates peritoneal senescence, inflammation, and fibrosis, highlighting its potential as a promising therapeutic strategy for peritoneal fibrosis.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402382R","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The FASEB Journal","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1096/fj.202402382R","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Targeting MLL1/WDR5-Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a
Peritoneal fibrosis poses a significant challenge to the long-term efficacy of peritoneal dialysis (PD), with emerging evidence highlighting the role of cellular senescence in its pathogenesis. p16INK4a is a cell cycle regulator that has been implicated in cellular senescence. Mixed-lineage leukemia 1 (MLL1) forms a complex with WD-40 repeat protein 5 (WDR5) and exhibits histone H3K4 methyltransferase activity. We have previously shown that inhibition of the MLL1/WDR5 complex reduces p16INK4a expression and attenuates renal senescence after injury in mice. This study aimed to investigate whether inhibiting MLL1/WDR5 attenuates peritoneal senescence, inflammation, and fibrosis in both human samples and in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO-injected mice), while also exploring the associated underlying mechanisms. MLL1/WDR5, histone 3 lysine 4 trimethylation (H3K4me3), and p16INK4a expression were elevated in TGF-β1-stimulated human peritoneal mesothelial cells (HPMCs), non-adherent cells obtained from patients undergoing PD, and the submesothelial compact zones of MGO-injected mice. Notably, p16INK4a expression in these cells was positively correlated with the dialysate/plasma creatinine ratio. Treatment with the MLL1/WDR5 protein–protein interaction inhibitors MM-102 and OICR-9429 reduced H3K4me3 levels and p16INK4a expression, suppressing fibrosis in HPMCs as well as peritoneal fibrosis and inflammation in MGO-injected mice. These inhibitors also improved peritoneal function in MGO-injected mice. Additionally, we demonstrated that MLL1/WDR5-induced H3K4me3 directly regulates p16INK4a gene transcription, and that inhibiting MLL1/WDR5 reduces H3K4me3, thereby suppressing p16INK4a gene transcription. These findings suggest that targeting MLL1/WDR5 activation alleviates peritoneal senescence, inflammation, and fibrosis, highlighting its potential as a promising therapeutic strategy for peritoneal fibrosis.
期刊介绍：
The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.
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