UHRF1 deficiency exacerbates intestinal inflammation by epigenetic modulation of NPY1R gene methylation

TL;DR

This study shows that UHRF1 deficiency worsens intestinal inflammation by altering the methylation of the NPY1R gene, offering new insights for IBD treatment.

Contribution

The study identifies a novel epigenetic regulatory axis involving UHRF1 and NPY1R in inflammatory bowel disease.

Findings

UHRF1 deficiency leads to increased NPY1R expression and worsened intestinal inflammation.

UHRF1 regulates NPY1R through promoter methylation, affecting cAMP/PKA/CREB and NF-κB signaling.

miR-141 is identified as a potential therapeutic agent by negatively regulating NPY1R.

Abstract

Epigenetic modifications play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) by mediating gene-environment interactions. We previously showed that UHRF1, a central regulator of DNA methylation, contributes to cancer progression; however, its function in IBD remains poorly understood. Here, we revealed that UHRF1 was frequently reduced in inflamed tissues of patients with IBD and that its deficiency exacerbated intestinal epithelial cell (IEC) damage. Through a multilevel approach incorporating human cell models and an intestinal epithelial-specific Uhrf1-KO mouse model, we established UHRF1 as a key mitigator of IBD progression. Mechanistically, UHRF1 bound to the NPY1R promoter, promoted its methylation, and led to transcriptional suppression. The NPY1R upregulation resulting from UHRF1 deficiency attenuated cAMP/PKA/CREB signaling in IECs, thereby enhancing NF-κB activation and subsequent proinflammatory responses, which compromised intestinal epithelial barrier integrity. Furthermore, we identified miR-141 as a negative regulator of NPY1R, highlighting its potential as a therapeutic agent. Collectively, our results identified the UHRF1/NPY1R regulatory axis as a critical epigenetic mechanism in intestinal inflammation and underscored its dual promise for IBD diagnostics and therapy.

UHRF1 shows potential as a novel diagnostic tool for IBD patients and lays the groundwork for developing microRNA-based therapeutic strategies targeting UHRF1 in IBD treatment.

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