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

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...

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Autores principales: Danan, Charles H., Naughton, Kaitlyn E., Hayer, Katharina E., Vellappan, Sangeevan, McMillan, Emily A., Zhou, Yusen, Matsuda, Rina, Nettleford, Shaneice K., Katada, Kay, Parham, Louis R., Ma, Xianghui, Chowdhury, Afrah, Wilkins, Benjamin J., Shah, Premal, Weitzman, Matthew D., Hamilton, Kathryn E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104132/
https://www.ncbi.nlm.nih.gov/pubmed/37066277
http://dx.doi.org/10.1101/2023.04.06.535853
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author Danan, Charles H.
Naughton, Kaitlyn E.
Hayer, Katharina E.
Vellappan, Sangeevan
McMillan, Emily A.
Zhou, Yusen
Matsuda, Rina
Nettleford, Shaneice K.
Katada, Kay
Parham, Louis R.
Ma, Xianghui
Chowdhury, Afrah
Wilkins, Benjamin J.
Shah, Premal
Weitzman, Matthew D.
Hamilton, Kathryn E.
author_facet Danan, Charles H.
Naughton, Kaitlyn E.
Hayer, Katharina E.
Vellappan, Sangeevan
McMillan, Emily A.
Zhou, Yusen
Matsuda, Rina
Nettleford, Shaneice K.
Katada, Kay
Parham, Louis R.
Ma, Xianghui
Chowdhury, Afrah
Wilkins, Benjamin J.
Shah, Premal
Weitzman, Matthew D.
Hamilton, Kathryn E.
author_sort Danan, Charles H.
collection PubMed
description 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.
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spelling pubmed-101041322023-04-15 Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival Danan, Charles H. Naughton, Kaitlyn E. Hayer, Katharina E. Vellappan, Sangeevan McMillan, Emily A. Zhou, Yusen Matsuda, Rina Nettleford, Shaneice K. Katada, Kay Parham, Louis R. Ma, Xianghui Chowdhury, Afrah Wilkins, Benjamin J. Shah, Premal Weitzman, Matthew D. Hamilton, Kathryn E. bioRxiv Article 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. Cold Spring Harbor Laboratory 2023-04-21 /pmc/articles/PMC10104132/ /pubmed/37066277 http://dx.doi.org/10.1101/2023.04.06.535853 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Danan, Charles H.
Naughton, Kaitlyn E.
Hayer, Katharina E.
Vellappan, Sangeevan
McMillan, Emily A.
Zhou, Yusen
Matsuda, Rina
Nettleford, Shaneice K.
Katada, Kay
Parham, Louis R.
Ma, Xianghui
Chowdhury, Afrah
Wilkins, Benjamin J.
Shah, Premal
Weitzman, Matthew D.
Hamilton, Kathryn E.
Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival
title Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival
title_full Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival
title_fullStr Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival
title_full_unstemmed Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival
title_short Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival
title_sort intestinal transit amplifying cells require mettl3 for growth factor signaling, kras expression, and cell survival
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104132/
https://www.ncbi.nlm.nih.gov/pubmed/37066277
http://dx.doi.org/10.1101/2023.04.06.535853
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