N6-methyladenosine (m6A) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, play important roles in tuning the chromatin state and transcription. Among diverse RNA-chromatin interacting modes, the nuclear RNA scaffold is considered important for trans-interactions but has not yet been connected with m6A yet. Here, we found that Ythdc1 played indispensable roles in the embryonic stem cell (ESC) self-renewal and differentiation potency, and these roles highly depended on its m6A-binding ability. Ythdc1 deficiency in ESCs resulted in decreased rRNA synthesis and the activation of 2-cell (2C) embryo-specific transcriptional program, and these observations recapitulated the transcriptome defects induced by dysfunction of the long interspersed nuclear element-1 (LINE1)-scaffold, which were unrelated to the direct targeting of Ythdc1. A detailed analysis revealed that Ythdc1 recognized m6A on LINE1 and was physically involved in the formation of the LINE1- Nucleolin partnership and the chromatin recruitment of Kap1. In summary, our study reveals a new link between m6A and the RNA scaffold and thus provides a new regulatory model for the crosstalk between RNA and the chromatin epigenome.

中文翻译：

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核m6A阅读器Ythdc1调节小鼠ESC中LINE1的支架功能

染色体相关调节性RNA（carRNA）上的N6-甲基腺苷（m6A），包括重复RNA，在调节染色质状态和转录中起重要作用。在多种RNA染色质相互作用模式中，核RNA支架被认为对反式相互作用很重要，但尚未与m6A连接。在这里，我们发现Ythdc1在胚胎干细胞（ESC）的自我更新和分化能力中起着不可或缺的作用，而这些作用高度依赖于其m6A结合能力。ESC中的Ythdc1缺乏导致rRNA合成减少和2细胞（2C）胚胎特异性转录程序的激活，这些观察概括了由长散布的核元素1（LINE1）支架功能异常引起的转录组缺陷，与直接定位Ythdc1无关。详细分析显示，Ythdc1识别LINE1上的m6A，并物理参与LINE1- Nucleolin伙伴关系的形成和Kap1的染色质募集。总而言之，我们的研究揭示了m6A与RNA支架之间的新联系，从而为RNA与染色质表观基因组之间的串扰提供了新的调控模型。