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Targeting NAT10 alleviates colonic senescence and elderly-onset colitis by disrupting N4-acetylation of DYRK1A
Jingyu Chen1,2,3,4, Meng Xue1,2,3, Shuyi Mi1,2,3
1Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Abstract:
Intestinal aging characterized by imbalance between cell senescence and mucosal self-renewal, increases susceptibility to the elderly-onset ulcerative colitis (UC), while the underlying mechanisms remain elusive. Here, we identify mRNA N4-acetylcytidine (ac4C) modification and its specific writer, N-acetyltransferase 10 (NAT10), as critical regulators of human colonic epithelial cell senescence. Knockdown of NAT10 significantly alleviates human colonic epithelial cell senescence in vitro and colonoid and intestinal aging in vivo in aged mice. Using ac4C-modified transcriptome sequencing, we reveal that NAT10 stabilizes DYRK1A mRNA through ac4C modification, thereby driving colon epithelial senescence. Moreover, NAT10 and DYRK1A are markedly upregulated in ulcerative colitis tissues from elderly patients and positively correlate with disease severity. Knockdown of NAT10, treatment with Nat10 or Dyrk1a inhibitor, alleviates colitis in aged mice. Collectively, these findings suggest that modulating NAT10-mediated RNA ac4C modification could rejuvenate intestinal aging and provide a novel therapeutic strategy for elderly-onset colitis.
Insights
Scientists found that the N4-acetylcytidine (ac4C) modification, regulated by NAT10, drives colon cell senescence and intestinal aging. Targeting NAT10 could reverse aging and treat elderly-onset ulcerative colitis.
Area of Science:
- Molecular Biology
- Gastroenterology
- Aging Research
Background:
- Intestinal aging, marked by senescence and reduced self-renewal, heightens susceptibility to elderly-onset ulcerative colitis (UC).
- The precise mechanisms driving this susceptibility remain largely unknown.
- Cellular senescence is a key factor in age-related diseases.
Purpose of the Study:
- To investigate the role of mRNA N4-acetylcytidine (ac4C) modification and its writer, N-acetyltransferase 10 (NAT10), in human colonic epithelial cell senescence.
- To explore the potential of targeting the NAT10 pathway as a therapeutic strategy for elderly-onset UC and intestinal aging.
Main Methods:
- Studied the impact of NAT10 knockdown on human colonic epithelial cell senescence in vitro and intestinal aging in aged mice.
- Employed ac4C-modified transcriptome sequencing to identify NAT10-regulated genes.
- Analyzed NAT10 and DYRK1A expression in UC tissues from elderly patients.
- Investigated the therapeutic effects of NAT10 inhibition and DYRK1A inhibition in aged mice with colitis.
Main Results:
- NAT10 was identified as a critical regulator of human colonic epithelial cell senescence.
- NAT10 knockdown alleviated senescence in vitro and intestinal aging in vivo.
- NAT10 stabilizes DYRK1A mRNA via ac4C modification, promoting colon epithelial senescence.
- NAT10 and DYRK1A were upregulated in elderly UC patients' tissues and correlated with disease severity.
- Inhibition of NAT10 or DYRK1A ameliorated colitis in aged mice.
Conclusions:
- NAT10-mediated RNA ac4C modification is a key driver of colon epithelial cell senescence and intestinal aging.
- Modulating NAT10 activity offers a promising therapeutic avenue for rejuvenating the aging intestine.
- This pathway presents a novel strategy for treating elderly-onset ulcerative colitis.
