Sisino Giorgia, Zhou Alex-Xianghua, Dahr Niklas, Sabirsh Alan, Soundarapandian Mangala M, Perera Ranjan, Larsson-Lekholm Erik, Magnone Maria Chiara, Althage Magnus, Tyrberg Björn
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
PLoS One. 2017 Aug 10;12(8):e0182371. doi: 10.1371/journal.pone.0182371. eCollection 2017.
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.
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.
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.
妊娠与催乳素驱动的β细胞增殖增加有关。长链非编码RNA（lncRNA）是哺乳动物基因组中最丰富的RNA种类，然而，它们的功能重要性主要仍不明确。
目的/假设：本研究检验这样一个假设，即在妊娠期间β细胞质量补偿的背景下，lncRNA响应催乳素调节β细胞增殖。
采用生物信息学方法探究妊娠第14.5天小鼠胰岛中lncRNA的表达谱，通过定量PCR在妊娠不同天数进一步证实，并通过比较胰岛与其他组织中的表达来评估胰岛特异性。为了确定候选lncRNA的作用，我们通过EdU掺入和细胞计数研究了小鼠胰岛和MIN6β细胞系中的细胞增殖。
我们发现一组lncRNA在妊娠第14.5天的小鼠胰岛中受到差异调节。在妊娠的不同阶段，这些lncRNA动态表达，并且在小鼠胰岛和MIN6细胞中其表达依赖于催乳素。其中一种lncRNA，Gm16308（Lnc03），在妊娠期间受到动态调节，依赖于催乳素且在胰岛中富集。在原代β细胞和MIN6细胞中沉默Lnc03会抑制增殖，而过度表达则会刺激增殖，即使在没有催乳素的情况下也是如此，这表明Lnc03调节β细胞生长。
结论/解读：在妊娠期间，小鼠胰岛增殖与lncRNA表达的动态变化相关。特别是，Lnc03调节小鼠β细胞增殖，并且可能是健康和疾病状态下β细胞质量适应中β细胞增殖的关键组成部分。
