Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
Stem Cell Core, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
Cell Commun Signal. 2023 Sep 5;21(1):229. doi: 10.1186/s12964-023-01212-2.
Our recent studies have demonstrated the crucial involvement of FOXA2 in the development of human pancreas. Reduction of FOXA2 expression during the differentiation of induced pluripotent stem cells (iPSCs) into pancreatic islets has been found to reduce α-and β-cell masses. However, the extent to which such changes are linked to alterations in the expression profile of long non-coding RNAs (lncRNAs) remains unraveled.
Here, we employed our recently established FOXA2-deficient iPSCs (FOXA2 iPSCs) to investigate changes in lncRNA profiles and their correlation with dysregulated mRNAs during the pancreatic progenitor (PP) and pancreatic islet stages. Furthermore, we constructed co-expression networks linking significantly downregulated lncRNAs with differentially expressed pancreatic mRNAs.
Our results showed that 442 lncRNAs were downregulated, and 114 lncRNAs were upregulated in PPs lacking FOXA2 compared to controls. Similarly, 177 lncRNAs were downregulated, and 59 lncRNAs were upregulated in islet cells lacking FOXA2 compared to controls. At both stages, we observed a strong correlation between lncRNAs and several crucial pancreatic genes and TFs during pancreatic differentiation. Correlation analysis revealed 12 DE-lncRNAs that strongly correlated with key downregulated pancreatic genes in both PPs and islet cell stages. Selected DE-lncRNAs were validated using RT-qPCR.
Our data indicate that the observed defects in pancreatic islet development due to the FOXA2 loss is associated with significant alterations in the expression profile of lncRNAs. Therefore, our findings provide novel insights into the role of lncRNA and mRNA networks in regulating pancreatic islet development, which warrants further investigations. Video Abstract.
我们最近的研究表明，FOXA2 在人类胰腺的发育中起着至关重要的作用。在诱导多能干细胞（iPSC）分化为胰岛的过程中，FOXA2 表达的减少会导致α和β细胞数量的减少。然而，这种变化与长链非编码 RNA（lncRNA）表达谱的改变之间的关联程度仍有待阐明。
在这里，我们利用我们最近建立的 FOXA2 缺陷型 iPSC（FOXA2 iPSC）来研究 lncRNA 谱的变化及其与胰腺祖细胞（PP）和胰岛阶段中失调的 mRNAs 之间的相关性。此外，我们构建了与差异表达的胰腺 mRNAs 相关的显著下调的 lncRNAs 的共表达网络。
我们的结果表明，与对照组相比，FOXA2 缺失的 PP 中 442 个 lncRNA 下调，114 个 lncRNA 上调。同样，与对照组相比，FOXA2 缺失的胰岛细胞中 177 个 lncRNA 下调，59 个 lncRNA 上调。在这两个阶段，我们观察到 lncRNA 与胰腺分化过程中的几个关键胰腺基因和 TF 之间存在很强的相关性。相关性分析显示，在 PP 和胰岛细胞阶段，有 12 个 DE-lncRNA 与关键下调的胰腺基因强烈相关。选择的 DE-lncRNA 使用 RT-qPCR 进行验证。
我们的数据表明，由于 FOXA2 缺失导致的胰岛发育缺陷与 lncRNA 表达谱的显著改变有关。因此，我们的发现为 lncRNA 和 mRNA 网络在调节胰岛发育中的作用提供了新的见解，值得进一步研究。
