PUBLICATION
β-Cell pre-miR-21 Induces Dysfunction and Loss of Cellular Identity by Targeting Transforming Growth Factor Beta 2 (Tgfb2) and Smad Family Member 2 (Smad2) mRNAs
- Authors
- Ibrahim, S., Johnson, M., Stephens, C.H., Xu, J., Moore, R., Mariani, A., Contreras, C., Syed, F., Mirmira, R.G., Anderson, R.M., Sims, E.K.
- ID
- ZDB-PUB-210713-5
- Date
- 2021
- Source
- Molecular metabolism 53: 101289 (Journal)
- Registered Authors
- Keywords
- dedifferentiation, identity, islet, microRNA 21, β-cell, β-cell dysfunction
- MeSH Terms
-
- Animals
- Humans
- Insulin-Secreting Cells/metabolism*
- Mice
- MicroRNAs/genetics
- MicroRNAs/metabolism*
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats
- Smad2 Protein/genetics
- Smad2 Protein/metabolism*
- Transforming Growth Factor beta2/genetics
- Transforming Growth Factor beta2/metabolism*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 34246804 Full text @ Mol Metab
Citation
Ibrahim, S., Johnson, M., Stephens, C.H., Xu, J., Moore, R., Mariani, A., Contreras, C., Syed, F., Mirmira, R.G., Anderson, R.M., Sims, E.K. (2021) β-Cell pre-miR-21 Induces Dysfunction and Loss of Cellular Identity by Targeting Transforming Growth Factor Beta 2 (Tgfb2) and Smad Family Member 2 (Smad2) mRNAs. Molecular metabolism. 53:101289.
Abstract
Objective β-cell microRNA-21 (miR-21) is increased by islet inflammatory stress and decreases glucose stimulated insulin secretion (GSIS). Thus, we sought to define the effects of miR-21 on β-cell function using in vitro and in vivo systems.
Methods We developed a tetracycline-on system of pre-miR-21 induction in clonal β-cells and human islets, as well as transgenic zebrafish and mouse models of β-cell specific pre-miR-21 overexpression.
Results β-cell miR-21 induction markedly reduced GSIS and led to reductions in transcription factors associated with β-cell identity and increases in markers of dedifferentiation, leading us to hypothesize that miR-21 induces β-cell dysfunction via loss of cell identity. In silico analysis identified Transforming Growth Factor Beta 2 (Tgfb2) and Smad Family Member 2 (Smad2) mRNAs as predicted miR-21 targets associated with maintenance of β-cell identity. Tgfb2 and Smad2 were confirmed as direct miR-21 targets via RT-PCR, immunoblot, pulldown and luciferase assays. In vivo zebrafish and mouse models exhibited glucose intolerance and decreased peak GSIS, decreased expression of β-cell identity markers, increased insulin and glucagon co-staining cells, and reduced Tgfb2 and Smad2 expression.
Conclusions These findings implicate miR-21-mediated reduction of mRNAs specifying β-cell identity as a contributor to β-cell dysfunction via loss of cellular differentiation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping