N6-adenomethylation of GsdmC is essential for Lgr5+ stem cell survival to maintain normal colonic epithelial morphogenesis

Du, Jie; Sarkar, Rajesh; Li, Yan; He, Lei; Kang, Wenjun; Liu, Weicheng; Nguyen, Tivoli; Zhang, Linda; Deng, Zuhu; Dougherty, Urszula; Kupfer, Sonia S.; Chen, Mengjie; Pekow, Joel; Bissonnette, Marc; He, Chuan; Li, Yan Chun

doi:10.1016/j.devcel.2022.07.006

Cited by 14 publications

(20 citation statements)

References 94 publications

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“…VilCreΔ/Δ mice was in stark contrast to Villin-Cre;Mettl14fl/fl mice described in recent studies (26,27). Villin-Cre;Mettl14fl/fl mice display significant epithelial abnormalities in the colon only, despite presumed loss of METTL14 in the small intestine since Villin-Cre targets both small intestine and colon.…”

Section: Mettl3mentioning

confidence: 72%

“…VilCreERΔ/Δ mice and published studies with METTL14 deletion in the intestinal epithelium (26,27). Finally, the absent inflammatory phenotype in Mettl3 VilCreERΔ/Δ mice contrasts with published data in mice with METTL14 deletion in the intestinal epithelium.…”

Section: Mettl3mentioning

confidence: 73%

“…Finally, the absent inflammatory phenotype in Mettl3 VilCreERΔ/Δ mice contrasts with published data in mice with METTL14 deletion in the intestinal epithelium. Intestinal epithelial METTL14 KO mice demonstrated extensive neutrophilic invasion of colonic mucosa, elevated cytokine markers in the colonic mucosa and serum, and complete rescue of mortality with antibiotic-mediated microbial depletion (27).…”

Section: Mettl3mentioning

confidence: 97%

“…To assess epithelial damage, we applied a composite histopathological score for small intestinal and colonic tissue that included grading of immune cell infiltration, depth of tissue damage, degree of regeneration, extent of crypt and villus degradation, and percent of total tissue involvement. Based on previous studies describing no overt pathology in METTL14depleted small intestinal epithelium (26,27), we expected to find minimal small intestinal defects in…”

Section: Mettl3mentioning

confidence: 99%

“…These studies found essential functions for METTL14 in the survival of intestinal stem cells and maintenance of epithelial integrity. Intriguingly, these dramatic phenotypes were restricted to the colonic epithelium, and the small intestinal epithelium was spared despite deletion of METTL14 in that tissue as well (26,27). METTL3 has not been investigated in homeostasis of the intestinal epithelium beyond one study that examined METTL3 deletion in the infection of mouse pups.…”

Section: Main Text Introductionmentioning

confidence: 99%

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Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival

Danan

Naughton

Hayer

et al. 2023

Preprint

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The METTL3-METTL14 methyltransferase complex adds N6-methyladenosine (m6A) to mRNA with profound impacts on cell fate. Studies delete METTL3 or METTL14 interchangeably to define the role of m6A in target tissues despite a lack of data confirming that these deletions are equivalent. Intestinal epithelial METTL14 deletion triggers stem cell death in the colon with no overt phenotype in the small intestine. The effect of METTL3 deletion in the same tissues remains unknown. We report that intestinal epithelial METTL3 deletion caused unexpected severe defects in the small intestine, including crypt and villus atrophy associated with cellular senescence and death in the crypt transit amplifying zone. Ribosome profiling and m6A-sequencing demonstrated downregulated translation of hundreds of unique methylated transcripts, including genes essential to growth factor signal transduction, such as Kras. Our study suggests that METTL3 is essential for small intestinal homeostasis via enhanced translation of growth factor signaling in crypt transit amplifying cells.

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Section: Mettl3mentioning

confidence: 72%

Section: Mettl3mentioning

confidence: 73%

Section: Mettl3mentioning

confidence: 97%

Section: Mettl3mentioning

confidence: 99%

Section: Main Text Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival

Danan

Naughton

Hayer

et al. 2023

Preprint

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Mettl14‐mediated m⁶A modification regulates the abnormal differentiation of small intestinal epithelial stem cells in diabetic state

Shan

Han

Song

et al. 2023

Journal Cellular Physiology

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Diabetes mellitus (DM) and its related complications are a global epidemic characterized by high morbidity and mortality. However, little is known about diabetic enteropathy (DE) and its the potential underlying mechanism. Intestinal epithelial stem cells (IESCs) were harvested from experimental mice, and the levels of dominant N6‐methyladenosine (m6A)‐related enzyme were detected by RT‐PCR, Western blotting, immunohistochemistry. The role of Mettl14 in the abnormal differentiation of intestinal epithelial cells (IECs) during DM was confirmed by knockdown experiments. RT‐PCR, MeRIP, and bioinformatics analysis were carried out to confirm the downstream target of Mettl14. Through bioinformatics analysis, RT‐PCR, and Western blotting, we further analyzed the differentiation‐related gene in the IECs from mice with DM. In this study, the levels of Mettl14 and m6A were higher in db/db mice than that in control mice. And abnormal differentiation of IECs in DM was associated with Mettl14 overexpression. Additionally, Mettl14 is a major determinant of IESCs identity and organoid‐forming upon DM state. Mechanistically, we revealed that the candidate binding target of Mettl14 was Fzd2 mRNA and affected Fzd2 stability. Moreover, Mettl14 downregulation was observed to attenuate the abnormal differentiation of IECs through modulating Fzd2 m6A modification in DM state. Together, our results provide definitive evidence for the essential role of Mettl14 in differentiation of IESCs in DM state.

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Multifaceted Functions of RNA m6A Modification in Modulating Regulated Cell Death

Zhan,

Liu,

Lin

et al. 2023

RNA Technologies

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N6-adenomethylation of GsdmC is essential for Lgr5+ stem cell survival to maintain normal colonic epithelial morphogenesis

Cited by 14 publications

References 94 publications

Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival

Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival

Mettl14‐mediated m⁶A modification regulates the abnormal differentiation of small intestinal epithelial stem cells in diabetic state

Multifaceted Functions of RNA m6A Modification in Modulating Regulated Cell Death

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N6-adenomethylation of GsdmC is essential for Lgr5+ stem cell survival to maintain normal colonic epithelial morphogenesis

Cited by 14 publications

References 94 publications

Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival

Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival

Mettl14‐mediated m6A modification regulates the abnormal differentiation of small intestinal epithelial stem cells in diabetic state

Multifaceted Functions of RNA m6A Modification in Modulating Regulated Cell Death

Contact Info

Product

Resources

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Mettl14‐mediated m⁶A modification regulates the abnormal differentiation of small intestinal epithelial stem cells in diabetic state