A desert lncRNA HIDEN regulates human endoderm differentiation via interacting with IMP1 and stabilizing FZD5 mRNA

Abstract

AbstractBackgroundExtensive 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(humanIMP1-associated "desert" definitiveendoderm lncRNA), in definitive endoderm differentiation from human pluripotent stem cells.ResultsWe 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 lncRNAHIDENwhich is upregulated and plays a vital role during human endoderm differentiation. We find depletion ofHIDENby either shRNA or promoter deletion significantly impairs human endoderm differentiation.HIDENfunctionally interacts with RNA-binding protein IMP1 (IGF2BP1), which is also required for endoderm differentiation. Loss ofHIDENor IMP1 results in reduced WNT activity, and WNT agonist rescues endoderm differentiation deficiency caused by the depletion ofHIDENor IMP1. Moreover,HIDENdepletion reduces the interaction between IMP1 protein andFZD5mRNA and causes the destabilization ofFZD5mRNA, which is a WNT receptor and necessary for definitive endoderm differentiation.ConclusionsThese data suggest that desert lncRNAHIDENfacilitates the interaction between IMP1 andFZD5mRNA, stabilizingFZD5mRNA which activates WNT signaling and promotes human definitive endoderm differentiation.