Program in Cell & Molecular Biology, Colorado State University, Fort Collins, Colorado 80523, USA.
Department of Microbiology, Immunology & Pathology.
RNA. 2020 Jun;26(6):739-755. doi: 10.1261/rna.073502.119. Epub 2020 Mar 13.
-methyladenosine (mA) is an abundant post-transcriptional modification that can impact RNA fate via interactions with mA-specific RNA binding proteins. Despite accumulating evidence that mA plays an important role in modulating pluripotency, the influence of mA reader proteins in pluripotency is less clear. Here, we report that YTHDF2, an mA reader associated with mRNA degradation, is highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation. Through RNA sequencing, we identified a group of mA-modified transcripts associated with neural development that are directly regulated by YTDHF2. Depletion of YTHDF2 in iPSCs leads to stabilization of these transcripts, loss of pluripotency, and induction of neural-specific gene expression. Collectively, our results suggest YTHDF2 functions to restrain expression of neural-specific mRNAs in iPSCs and facilitate their rapid and coordinated up-regulation during neural induction. These effects are both achieved by destabilization of the targeted transcripts.
m6A 是一种丰富的转录后修饰，可通过与 m6A 特异性 RNA 结合蛋白相互作用来影响 RNA 命运。尽管越来越多的证据表明 m6A 在调节多能性方面发挥着重要作用，但 m6A 读蛋白在多能性中的影响尚不清楚。在这里，我们报告说，与 mRNA 降解相关的 m6A 阅读器 YTHDF2 在诱导多能干细胞（iPSCs）中高度表达，并在神经分化过程中下调。通过 RNA 测序，我们鉴定了一组与神经发育相关的 m6A 修饰转录本，这些转录本直接受 YTDHF2 调控。在 iPSCs 中耗尽 YTHDF2 会导致这些转录本的稳定性增加，多能性丧失，并诱导神经特异性基因表达。总的来说，我们的结果表明，YTHDF2 的功能是抑制 iPSCs 中神经特异性 mRNA 的表达，并促进它们在神经诱导过程中快速协调地上调。这些作用都是通过靶向转录本的不稳定性来实现的。
