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UHRF1 Deficiency Exacerbates Intestinal Inflammation by Epigenetic Modulation of NPY1R Gene Methylation

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 is frequently reduced in inflamed tissues of IBD patients and that its deficiency exacerbates intestinal epithelial cell (IEC) damage. Through a multi-level approach incorporating human cell models and an intestinal epithelial-specific Uhrf1 knockout mouse model, we established UHRF1 as a key mitigator of IBD progression. Mechanistically, UHRF1 bound to the NPY1R promoter, promoting its methylation and leading to transcriptional suppression. The NPY1R upregulation resulting from UHRF1 deficiency attenuated cAMP–PKA–CREB signaling in IECs, thereby enhancing NF-κB activation and subsequent pro-inflammatory 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310605 | GEO | 2025/11/22

REPOSITORIES: GEO

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UHRF1 Deficiency Exacerbates Intestinal Inflammation by Epigenetic Modulation of NPY1R Gene Methylation [gene expression]

Project description: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 is frequently reduced in inflamed tissues of IBD patients and that its deficiency exacerbates intestinal epithelial cell (IEC) damage. Through a multi-level approach incorporating human cell models and an intestinal epithelial-specific Uhrf1 knockout mouse model, we established UHRF1 as a key mitigator of IBD progression. Mechanistically, UHRF1 bound to the NPY1R promoter, promoting its methylation and leading to transcriptional suppression. The NPY1R upregulation resulting from UHRF1 deficiency attenuated cAMP–PKA–CREB signaling in IECs, thereby enhancing NF-κB activation and subsequent pro-inflammatory 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.

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UHRF1 Deficiency Exacerbates Intestinal Inflammation by Epigenetic Modulation of NPY1R Gene Methylation

Project description:UHRF1 Deficiency Exacerbates Intestinal Inflammation by Epigenetic Modulation of NPY1R Gene Methylation

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