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Circular RNA circHIPK3 promotes homeostasis of the intestinal epithelium by reducing miR-29b function
- Source :
- Gastroenterology
- Publication Year :
- 2021
-
Abstract
- Background & Aims Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that form covalently closed circles. Although circRNAs influence many biological processes, little is known about their role in intestinal epithelium homeostasis. We surveyed circRNAs required to maintain intestinal epithelial integrity and identified circular homeodomain-interacting protein kinase 3 (circHIPK3) as a major regulator of intestinal epithelial repair after acute injury. Methods Intestinal mucosal tissues were collected from mice exposed to cecal ligation and puncture for 48 hours and patients with inflammatory bowel diseases and sepsis. We isolated primary enterocytes from the small intestine of mice and derived intestinal organoids. The levels of circHIPK3 were silenced in intestinal epithelial cells (IECs) by transfection with small interfering RNAs targeting the circularization junction of circHIPK3 or elevated using a plasmid vector that overexpressed circHIPK3. Intestinal epithelial repair was examined in an in vitro injury model by removing part of the monolayer. The association of circHIPK3 with microRNA 29b (miR-29b) was determined by biotinylated RNA pull-down assays. Results Genome-wide profile analyses identified ∼300 circRNAs, including circHIPK3, differentially expressed in the intestinal mucosa of mice after cecal ligation and puncture relative to sham mice. Intestinal mucosa from patients with inflammatory bowel diseases and sepsis had reduced levels of circHIPK3. Increasing the levels of circHIPK3 enhanced intestinal epithelium repair after wounding, whereas circHIPK3 silencing repressed epithelial recovery. CircHIPK3 silencing also inhibited growth of IECs and intestinal organoids, and circHIPK3 overexpression promoted intestinal epithelium renewal in mice. Mechanistic studies revealed that circHIPK3 directly bound to miR-29b and inhibited miR-29 activity, thus increasing expression of Rac1, Cdc42, and cyclin B1 in IECs after wounding. Conclusions In studies of mice, IECs, and human tissues, our results indicate that circHIPK3 improves repair of the intestinal epithelium at least in part by reducing miR-29b availability.
- Subjects :
- Male
rac1 GTP-Binding Protein
Small interfering RNA
Down-Regulation
RAC1
Biology
Article
Intestinal mucosa
Cell Movement
Sepsis
microRNA
medicine
Gene silencing
Animals
Homeostasis
Humans
Cyclin B1
Intestinal Mucosa
cdc42 GTP-Binding Protein
Cells, Cultured
Cell Proliferation
Wound Healing
Hepatology
Neuropeptides
Gastroenterology
RNA
Epithelial Cells
RNA, Circular
Inflammatory Bowel Diseases
Intestinal epithelium
Small intestine
Cell biology
Mice, Inbred C57BL
Intestines
Disease Models, Animal
MicroRNAs
medicine.anatomical_structure
Female
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....139746b350b7c07a98506466a1813592