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

التفاصيل البيبلوغرافية
العنوان: Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival.
المؤلفون: Danan CH; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Naughton KE; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Hayer KE; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, PA, 19104, USA., Vellappan S; Waksman Institute of Microbiology, Rutgers University, Piscataway, NJ, 08854, USA.; Department of Genetics, Rutgers University, Piscataway, NJ, 08854, USA.; Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA., McMillan EA; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Zhou Y; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Matsuda R; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Nettleford SK; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Katada K; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Parham LR; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Ma X; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Chowdhury A; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Wilkins BJ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, PA, 19104, USA., Shah P; Department of Genetics, Rutgers University, Piscataway, NJ, 08854, USA.; Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA., Weitzman MD; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, PA, 19104, USA., Hamilton KE; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 21. Date of Electronic Publication: 2023 Apr 21.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: Intestinal epithelial transit amplifying cells are essential stem progenitors required for intestinal homeostasis, but their rapid proliferation renders them vulnerable to DNA damage from radiation and chemotherapy. Despite their critical roles in intestinal homeostasis and disease, few studies have described genes that are essential to transit amplifying cell function. We report that the RNA methyltransferase, METTL3, is required for survival of transit amplifying cells in the murine small intestine. Transit amplifying cell death after METTL3 deletion was associated with crypt and villus atrophy, loss of absorptive enterocytes, and uniform wasting and death in METTL3-depleted mice. Ribosome profiling and sequencing of methylated RNAs in enteroids and in vivo demonstrated decreased translation of hundreds of unique methylated transcripts after METTL3 deletion, particularly transcripts involved in growth factor signal transduction such as Kras . Further investigation confirmed a novel relationship between METTL3 and Kras methylation and protein levels in vivo . Our study identifies METTL3 as an essential factor supporting the homeostasis of small intestinal tissue via direct maintenance of transit amplifying cell survival. We highlight the crucial role of RNA modifications in regulating growth factor signaling in the intestine, with important implications for both homeostatic tissue renewal and epithelial regeneration.
Competing Interests: Conflict-of-interest statement Premal Shah is a member of the Scientific Advisory Board of Trestle Biosciences and is Director at Ananke Therapeutics. All other authors declare they have no competing interests.
التعليقات: Update in: JCI Insight. 2023 Oct 26;:. (PMID: 37883185)
معلومات مُعتمدة: P30 DK050306 United States DK NIDDK NIH HHS; R01 DK124369 United States DK NIDDK NIH HHS; R21 ES031533 United States ES NIEHS NIH HHS
سلسلة جزيئية: Dryad 10.5061/dryad.5tb2rbp8s
تواريخ الأحداث: Date Created: 20230417 Latest Revision: 20231208
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC10104132
DOI: 10.1101/2023.04.06.535853
PMID: 37066277
قاعدة البيانات: MEDLINE
الوصف
DOI:10.1101/2023.04.06.535853