Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
Nucleic Acids Res. 2018 May 4;46(8):3906-3920. doi: 10.1093/nar/gky130.
Previous studies have revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in embryonic stem cells (ESCs), but the biological function of m6A in large intergenic noncoding RNA (lincRNA) is unknown. Here, we showed that the internal m6A modification of linc1281 mediates a competing endogenous RNA (ceRNA) model to regulate mouse ESC (mESC) differentiation. We demonstrated that loss of linc1281 compromises mESC differentiation and that m6A is highly enriched within linc1281 transcripts. Linc1281 with RRACU m6A sequence motifs, but not an m6A-deficient mutant, restored the phenotype in linc1281-depleted mESCs. Mechanistic analyses revealed that linc1281 ensures mESC identity by sequestering pluripotency-related let-7 family microRNAs (miRNAs), and this RNA-RNA interaction is m6A dependent. Collectively, these findings elucidated the functional roles of linc1281 and its m6A modification in mESCs and identified a novel RNA regulatory mechanism, providing a basis for further exploration of broad RNA epigenetic regulatory patterns.
先前的研究揭示了 mRNA 的 N6-甲基腺苷（m6A）修饰在胚胎干细胞（ESCs）中的关键作用，但长链非编码 RNA（lincRNA）中 m6A 的生物学功能尚不清楚。在这里，我们表明 linc1281 的内部 m6A 修饰介导竞争性内源 RNA（ceRNA）模型来调节小鼠胚胎干细胞（mESC）分化。我们证明了 linc1281 的缺失会损害 mESC 分化，并且 linc1281 转录本中高度富集了 m6A。具有 RRACU m6A 序列基序的 linc1281，但不是 m6A 缺陷突变体，可恢复 linc1281 耗尽的 mESC 中的表型。机制分析表明，linc1281 通过隔离多能性相关的 let-7 家族 microRNAs（miRNAs）来确保 mESC 特性，并且这种 RNA-RNA 相互作用依赖于 m6A。总之，这些发现阐明了 linc1281 及其在 mESCs 中的 m6A 修饰的功能作用，并确定了一种新的 RNA 调控机制，为进一步探索广泛的 RNA 表观遗传调控模式提供了基础。
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