Targeting MLL1/WDR5-Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16^INK4a

Area of Science:

• Cell Biology
• Molecular Biology
• Nephrology

Background:

• Peritoneal fibrosis is a major complication of peritoneal dialysis (PD).
• Cellular senescence, particularly p16INK4a expression, is increasingly recognized in peritoneal fibrosis pathogenesis.
• The Mixed-lineage leukemia 1 (MLL1)/WD-40 repeat protein 5 (WDR5) complex, a histone methyltransferase, influences gene expression and cellular processes.

Purpose of the Study:

• To investigate the role of MLL1/WDR5 in peritoneal senescence and fibrosis.
• To determine if inhibiting MLL1/WDR5 can attenuate peritoneal senescence, inflammation, and fibrosis.
• To explore the underlying molecular mechanisms involving p16INK4a and histone 3 lysine 4 trimethylation (H3K4me3).

Main Methods:

• Assessed MLL1/WDR5, H3K4me3, and p16INK4a expression in human peritoneal mesothelial cells (HPMCs), PD patient samples, and methylglyoxal (MGO)-induced mouse models.
• Utilized MLL1/WDR5 inhibitors (MM-102, OICR-9429) to treat cells and MGO-injected mice.
• Analyzed the correlation between p16INK4a expression and dialysate/plasma creatinine ratio.
• Investigated the direct regulatory role of MLL1/WDR5-induced H3K4me3 on p16INK4a gene transcription.

Main Results:

• Elevated MLL1/WDR5, H3K4me3, and p16INK4a were observed in stimulated HPMCs, PD patient cells, and MGO-induced mouse peritoneal tissue.
• MLL1/WDR5 inhibition significantly reduced H3K4me3 and p16INK4a levels.
• Treatment with inhibitors suppressed peritoneal fibrosis and inflammation in MGO-injected mice and improved peritoneal function.
• MLL1/WDR5-induced H3K4me3 was confirmed to directly regulate p16INK4a transcription.

Conclusions:

• Targeting the MLL1/WDR5 complex effectively reduces peritoneal senescence, inflammation, and fibrosis.
• Inhibition of MLL1/WDR5 offers a potential therapeutic strategy for mitigating peritoneal fibrosis in PD patients.
• The findings elucidate a novel mechanism involving MLL1/WDR5, H3K4me3, and p16INK4a in the development of peritoneal fibrosis.