Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Genome Biol. 2023 Apr 24;24(1):92. doi: 10.1186/s13059-023-02925-w.
Extensive studies have revealed the function and mechanism of lncRNAs in development and differentiation, but the majority have focused on those lncRNAs adjacent to protein-coding genes. In contrast, lncRNAs located in gene deserts are rarely explored. Here, we utilize multiple differentiation systems to dissect the role of a desert lncRNA, HIDEN (human IMP1-associated "desert" definitive endoderm lncRNA), in definitive endoderm differentiation from human pluripotent stem cells.
We show that desert lncRNAs are highly expressed with cell-stage-specific patterns and conserved subcellular localization during stem cell differentiation. We then focus on the desert lncRNA HIDEN which is upregulated and plays a vital role during human endoderm differentiation. We find depletion of HIDEN by either shRNA or promoter deletion significantly impairs human endoderm differentiation. HIDEN functionally interacts with RNA-binding protein IMP1 (IGF2BP1), which is also required for endoderm differentiation. Loss of HIDEN or IMP1 results in reduced WNT activity, and WNT agonist rescues endoderm differentiation deficiency caused by the depletion of HIDEN or IMP1. Moreover, HIDEN depletion reduces the interaction between IMP1 protein and FZD5 mRNA and causes the destabilization of FZD5 mRNA, which is a WNT receptor and necessary for definitive endoderm differentiation.
These data suggest that desert lncRNA HIDEN facilitates the interaction between IMP1 and FZD5 mRNA, stabilizing FZD5 mRNA which activates WNT signaling and promotes human definitive endoderm differentiation.
大量研究揭示了 lncRNA 在发育和分化中的功能和机制，但大多数研究都集中在那些位于蛋白编码基因附近的 lncRNA 上。相比之下，位于基因荒漠中的 lncRNA 则很少被研究。在这里，我们利用多种分化系统来剖析 HIDEN（人类 IMP1 相关“荒漠”定型内胚层 lncRNA）在人类多能干细胞向定型内胚层分化中的作用。
我们表明，荒漠 lncRNA 在细胞阶段具有高度表达的特征，并且在干细胞分化过程中具有保守的亚细胞定位。然后，我们将注意力集中在 HIDEN 上，它在人类内胚层分化过程中上调并发挥重要作用。我们发现，通过 shRNA 或启动子缺失敲低 HIDEN 会显著损害人类内胚层分化。HIDEN 与 RNA 结合蛋白 IMP1（IGF2BP1）具有功能相互作用，IMP1 也是内胚层分化所必需的。HIDEN 或 IMP1 的缺失会导致 WNT 活性降低，而 WNT 激动剂可以挽救因 HIDEN 或 IMP1 缺失导致的内胚层分化缺陷。此外，HIDEN 敲低会减少 IMP1 蛋白与 FZD5 mRNA 的相互作用，并导致 FZD5 mRNA 的不稳定性，FZD5 mRNA 是 WNT 受体，对于定型内胚层分化是必需的。
这些数据表明，荒漠 lncRNA HIDEN 促进了 IMP1 和 FZD5 mRNA 之间的相互作用，稳定了 FZD5 mRNA，从而激活了 WNT 信号通路，促进了人类定型内胚层分化。
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