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The Loss of YTHDC1 in Gut Macrophages Exacerbates Inflammatory Bowel Disease
Xuejun Ge1, Gang Xue2, Yan Ding3,4
1Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, 030001, China.
Abstract:
The nuclear N6 -methyladenosine (m6 A) reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required to maintain embryonic stem cell identity. However, little is known about its biological functions in intestinal-resident macrophages and inflammatory bowel disease (IBD). Herein, it is demonstrated that macrophage-specific depletion or insufficiency of YTHDC1 accelerates IBD development in animal models. On the molecular basis, YTHDC1 reduction in IBD-derived macrophages is attributed to Zinc finger protein 36 (ZFP36)-induced mRNA degradation. Importantly, transcriptome profiling and mechanistic assays unveil that YTHDC1 in macrophages regulates Ras homolog family member H (RHOH) to suppress inflammatory responses and fine-tunes NME nucleoside diphosphate kinase 1 (NME1) to enhance the integrity of colonic epithelial barrier, respectively. Collectively, this study identifies YTHDC1 as an important factor for the resolution of inflammatory responses and restoration of colonic epithelial barrier in the setting of IBD.
Insights
The nuclear m6 A reader YTHDC1 is crucial for intestinal macrophages in inflammatory bowel disease (IBD). Its deficiency accelerates IBD by impairing inflammation resolution and colonic barrier integrity.
Area of Science:
- Immunology
- Molecular Biology
- Gastroenterology
Background:
- Nuclear N6 -methyladenosine (m6 A) reader YT521-B homology-domain-containing protein 1 (YTHDC1) maintains stem cell identity.
- The role of YTHDC1 in intestinal macrophages and inflammatory bowel disease (IBD) remains largely unknown.
Purpose of the Study:
- To investigate the function of YTHDC1 in macrophages during IBD pathogenesis.
- To elucidate the molecular mechanisms underlying YTHDC1's role in intestinal inflammation.
Main Methods:
- Macrophage-specific YTHDC1 depletion in animal models of IBD.
- Transcriptome profiling of IBD-derived macrophages.
- Mechanistic assays to identify YTHDC1-regulated pathways.
Main Results:
- Macrophage-specific YTHDC1 insufficiency accelerates IBD development.
- YTHDC1 reduction in IBD macrophages is mediated by ZFP36-induced mRNA degradation.
- YTHDC1 regulates RHOH to suppress inflammation and NME1 to enhance colonic epithelial barrier integrity.
Conclusions:
- YTHDC1 is a critical regulator of macrophage function in IBD.
- YTHDC1 promotes the resolution of intestinal inflammation and maintains colonic barrier integrity.
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