Single Cell Analysis Reveals Multi-faceted miR-375 Regulation of the Intestinal Crypt
Single Cell Analysis Reveals Multi-faceted miR-375 Regulation of the Intestinal Crypt
Summary The role of individual miRNAs in small intestinal (SI) epithelial homeostasis is under-explored. In this study, we discovered that miR-375 is among the most enriched miRNAs in intestinal crypts and stem cells (ISCs), especially facultative ISCs. We then showed by multiple manipulations, including CRISPR/Cas9 editing, that miR-375 is strongly suppressed by Wnt-signaling. Single-cell RNA-seq analysis of SI crypt-enriched cells from miR-375 knockout (375-KO) mice revealed elevated numbers of tuft cells and increased expression of pro-proliferative genes in ISCs. Accordingly, the genetic loss of miR-375 promoted resistance to helminth infection and enhanced the regenerative response to irradiation. The conserved effects of miR-375 were confirmed by gain-of-function studies in Drosophila midgut stem cells in vivo. Moreover, functional experiments in enteroids uncovered a regulatory relationship between miR-375 and Yap1 that controls cell survival. Finally, analysis of mouse model and clinical data revealed an inverse association between miR-375 levels and intestinal tumor development. HighlightsmiR-375 is one of the most enriched miRNAs in ISCs, especially facultative ISCs.miR-375 modifies tuft cell abundance and pro-proliferative gene expression in ISCs.Loss of miR-375 in mice enhances the host response to helminth infection and crypt regeneration.Mouse and human intestinal cancer are associated with reduced miR-375 expression. eTOC BlurbSethupathy and colleagues show that miR-375 is a Wnt-responsive, ISC-enriched miRNA that serves as a break on intestinal crypt proliferation. They also show that miR-375 modulates tuft cell abundance and pro-proliferative gene expression in ISCs, that miR-375 loss enhances the host response to helminth infection as well as crypt regeneration post-irradiation, and its reduced expression is associated with intestinal cancer.
Rinaldi Vera D.、Dekaney Christopher M.、Villanueva Jonathan W.、McNairn Adrian J.、Oyesola Oyebola O.、Hung Yu-Han、Cubitt Rebecca L.、Sethupathy Praveen、Dow Lukas E.、Pitman Wendy A.、Sheahan Breanna、Shanahan Michael T.、Peck Bailey C.E.、Bloom Jordana C.、Bonfini Alessandro、Singh Ajeet P.、Curry Ennessa G.、Schimenti John C.、Kanke Matt、Ding Shengli、Tait-Wojno Elia D.、Buchon Nicolas
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Molecular Biomedical Sciences, North Carolina State UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityBaker Institute, College of Veterinary Medicine, Cornell UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversitySandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, Cornell UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Molecular Biomedical Sciences, North Carolina State UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Surgery, School of Medicine, University of MichiganDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityCornell Institute of Host-Microbe Interactions and Disease, Department of Entomology, Cornell UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Genetics, School of Medicine, University of North CarolinaDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell UniversityDepartment of Cell Biology and Physiology, School of Medicine, University of North CarolinaBaker Institute, College of Veterinary Medicine, Cornell UniversityCornell Institute of Host-Microbe Interactions and Disease, Department of Entomology, Cornell University
基础医学细胞生物学分子生物学
Rinaldi Vera D.,Dekaney Christopher M.,Villanueva Jonathan W.,McNairn Adrian J.,Oyesola Oyebola O.,Hung Yu-Han,Cubitt Rebecca L.,Sethupathy Praveen,Dow Lukas E.,Pitman Wendy A.,Sheahan Breanna,Shanahan Michael T.,Peck Bailey C.E.,Bloom Jordana C.,Bonfini Alessandro,Singh Ajeet P.,Curry Ennessa G.,Schimenti John C.,Kanke Matt,Ding Shengli,Tait-Wojno Elia D.,Buchon Nicolas.Single Cell Analysis Reveals Multi-faceted miR-375 Regulation of the Intestinal Crypt[EB/OL].(2025-03-28)[2025-05-05].https://www.biorxiv.org/content/10.1101/2020.10.01.321612.点此复制
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