Linc1548 promotes the transition of epiblast stem cells into neural progenitors by engaging OCT6 and SOX2

The transition of embryonic stem cells from the epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs), name as the neural induction process, is crucial for cell fate determination of neural differentiation. However, the mechanism of this transition is unclear. Here, we identified a long non-coding RNA (linc1548) as a critical regulator of neural differentiation of mouse embryonic stem cells (mESCs). Knockout of linc1548 did not affect the conversion of mESCs to EpiSCs, but delayed the transition from EpiSCs to NPCs. Moreover, linc1548 interacts with the transcription factors OCT6 and SOX2 forming an RNA-protein complex to regulate the transition from EpiSCs to NPCs. Finally, we showed that Zfp521 is an important target gene of this RNA-protein complex regulating neural differentiation. Our findings prove how the intrinsic transcription complex mediated by a lncRNA linc1548 and can better understand the intrinsic mechanism of neural fate determination. mRNA profiles of wild type (WT) and KO-Linc1548 46C cells at day 5 of neural differentiation were generated by microarray.

胚胎干细胞从上胚层干细胞（epiblast stem cells, EpiSCs）向神经前体细胞（neural progenitor cells, NPCs）的转变，即神经诱导过程，对神经分化的细胞命运决定至关重要。然而，这一转变的分子机制目前仍不明确。本研究鉴定出长链非编码RNA（long non-coding RNA, lncRNA）linc1548是小鼠胚胎干细胞（mouse embryonic stem cells, mESCs）神经分化的关键调控因子。敲除linc1548不会影响小鼠胚胎干细胞向其上胚层干细胞的转化，但会延缓上胚层干细胞向神经前体细胞的转变。此外，linc1548可与转录因子OCT6及SOX2结合形成RNA-蛋白质复合物，以此调控上胚层干细胞向神经前体细胞的转变。最后，本研究证实Zfp521是该RNA-蛋白质复合物调控神经分化的重要靶基因。本研究阐明了长链非编码RNA linc1548介导的内源性转录复合物的作用机制，有助于更深入地理解神经命运决定的内在分子机制。本研究通过微阵列（microarray）技术获取了神经分化第5天时野生型（wild type, WT）与敲除Linc1548的46C细胞的mRNA表达谱。