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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.

Citation
Ibrahim, S., et al. “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, p. 101289.
Center Indiana University
Author Sara Ibrahim, Macey Johnson, Clarissa Hernandez Stephens, Jerry Xu, Rachel Moore, Andrea Mariani, Christopher Contreras, Farooq Syed, Raghavendra G Mirmira, Ryan M Anderson, Emily K Sims
Keywords dedifferentiation, identity, islet, microRNA 21, β-Cell, β-cell dysfunction
Abstract

OBJECTIVE: β-cell microRNA-21 (miR-21) is increased by islet inflammatory stress but it 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, along with 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 increased markers of dedifferentiation, which led us to hypothesize that miR-21 induces β-cell dysfunction by 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 the maintenance of β-cell identity. Tgfb2 and Smad2 were confirmed as direct miR-21 targets through RT-PCR, immunoblot, pulldown, and luciferase assays. In vivo zebrafish and mouse models exhibited glucose intolerance, 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 by the loss of cellular differentiation.

Year of Publication
2021
Journal
Molecular metabolism
Volume
53
Number of Pages
101289
Date Published
11/2021
ISSN Number
2212-8778
DOI
10.1016/j.molmet.2021.101289
Alternate Journal
Mol Metab
PMID
34246804
PMCID
PMC8361274
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