Abstract
Pregnancy is associated with increased β-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 β-cell proliferation in response to prolactin in the context of β-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 β-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 β-cells and MIN6 cells inhibits, whereas over-expression stimulates, proliferation even in the absence of prolactin, demonstrating that Lnc03 regulates β-cell growth. Conclusions/interpretation: During pregnancy mouse islet proliferation is correlated with dynamic changes of lncRNA expression. In particular, Lnc03 regulates mouse β-cell proliferation and may be a crucial component of β-cell proliferation in β-cell mass adaptation in both health and disease.
Highlights
Compensatory mechanisms are present in adult β-cells to adapt to high metabolic physiological or pathophysiological demands, such as in pregnancy or obesity
The mouse islet transcriptome was analyzed by the NCode Long noncoding RNAs (lncRNA) microarray
According to our stringent statistical analysis, RNA-seq displayed higher sensitivity in detecting differentially expressed lncRNAs compared to the NCode array
Summary
Compensatory mechanisms are present in adult β-cells to adapt to high metabolic physiological or pathophysiological demands, such as in pregnancy or obesity. One consequence is that β-cell mass increases through cell replication, neogenesis, and hypertrophy [1]. Insulin resistance increases [3] and β-cells respond by increasing mass to supply sufficient insulin. Failure of this adaptation process leads to gestational diabetes and to the concomitant risk of developing type 2 diabetes [4]. Studies in rodents have shown that the peak of β-cell proliferation during gestation coincides with increased circulating placental hormones [5], in particular prolactin. The molecular machinery that drives β-cell mass expansion in response to pregnancy and prolactin has been partly elucidated, which involves protein coding genes as well as microRNAs [6]. The role of long noncoding RNAs (lncRNAs) has never been explored
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