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Long noncoding RNAs are dynamically regulated during beta-cell mass expansion in mouse pregnancy and control beta-cell proliferation in vitro

Journal article
Authors G. Sisino
A. X. Zhou
Niklas Dahr
A. Sabirsh
M. M. Soundarapandian
R. Perera
Erik Larsson
M. C. Magnone
M. Althage
B. Tyrberg
Published in Plos One
Volume 12
Issue 8
ISSN 1932-6203
Publication year 2017
Published at Institute of Biomedicine
Language en
Links doi.org/10.1371/journal.pone.018237...
Keywords GENE-EXPRESSION, PROLACTIN RECEPTORS, INSULIN-SECRETION, PANCREATIC-ISLETS, GROWTH-HORMONE, TRANSCRIPTION, LANGERHANS, PROMOTERS, SEROTONIN, GLUCOSE
Subject categories Cell and Molecular Biology

Abstract

Pregnancy is associated with increased beta-cell proliferation driven by prolactin. Long noncoding RNAs (lncRNA) are the most abundant RNA species in the mammalian genome, yet, their functional importance is mainly elusive. Aims/hypothesis: This study tests the hypothesis that lncRNAs regulate beta-cell proliferation in response to prolactin in the context of beta-cell mass compensation in pregnancy. Methods: The expression profile of lncRNAs in mouse islets at day 14.5 of pregnancy was explored by a bioinformatics approach, further confirmed by quantitative PCR at different days of pregnancy, and islet specificity was evaluated by comparing expression in islets versus other tissues. In order to establish the role of the candidate lncRNAs we studied cell proliferation in mouse islets and the MIN6 beta-cell line by EdU incorporation and cell count. Results: We found that a group of lncRNAs is differentially regulated in mouse islets at 14.5 days of pregnancy. At different stages of pregnancy, these lncRNAs are dynamically expressed, and expression is prolactin dependent in mouse islets and MIN6 cells. One of those lncRNAs, Gm16308 (Lnc03), is dynamically regulated during pregnancy, prolactin-dependent and islet-enriched. Silencing Lnc03 in primary beta-cells and MIN6 cells inhibits, whereas over-expression stimulates, proliferation even in the absence of prolactin, demonstrating that Lnc03 regulates beta-cell growth. Conclusions/interpretation: During pregnancy mouse islet proliferation is correlated with dynamic changes of lncRNA expression. In particular, Lnc03 regulates mouse beta-cell proliferation and may be a crucial component of beta-cell proliferation in beta-cell mass adaptation in both health and disease.

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