The RNA N6-methyladenosine regulates chromatin remodeling and transcription [seq_nuclearRNA]

The N6-methyladenosine (m6A) has been shown to regulate stability and translation of messenger RNA (mRNA) in various biological processes. Here, we show that the knockout of the m6A writer Mettl3 or a nuclear reader Ythdc1 in mouse embryonic stem cells (mESCs) induces chromatin openness and transcription activation in an m6A-dependent manner. We identified extensive m6A modifications on caRNAs (chromosome-associated RNAs, including promoter-associated RNAs, enhancer RNAs and repeats) that are installed by METTL3. YTHDC1 can bind to a portion of these m6A-modified RNAs and facilitate their decay through the NEXT-mediated nuclear degradation. Therefore, the m6A methylation of these caRNAs reduces their abundances. The knockout of Mettl3 elevates levels of caRNAs and promote open chromatin state and downstream transcription. Collectively, our results reveal that m6A on caRNAs can globally tune chromatin state and transcription. Examine nuclear non-ribosome RNA decay in ckoYTHDC1 and control mESCs, and gene expression in control and two knockout METTL3 mESCs

N6-甲基腺苷酸（N6-methyladenosine，m6A）已被证实可在多种生物学过程中调控信使RNA（messenger RNA，mRNA）的稳定性与翻译过程。本研究发现，在小鼠胚胎干细胞（mouse embryonic stem cells，mESCs）中敲除m6A写入酶METTL3或核阅读蛋白YTHDC1，会以m6A依赖的方式诱导染色质开放与转录激活。我们鉴定出了由METTL3催化修饰的、广泛存在于染色体相关RNA（chromosome-associated RNAs，caRNAs，包括启动子相关RNA、增强子RNA及重复序列RNA）上的m6A修饰。YTHDC1可结合其中一部分带有m6A修饰的RNA，并通过NEXT介导的核降解途径促进其降解。因此，这类caRNAs的m6A甲基化会降低其丰度。敲除METTL3会提升caRNAs的水平，并促进开放染色质状态与下游转录。综上，我们的研究结果揭示，caRNAs上的m6A修饰可全局性调控染色质状态与转录过程。本研究检测了YTHDC1条件性敲除（ckoYTHDC1）与对照mESCs中的核非核糖体RNA降解情况，以及对照与两种METTL3敲除mESCs中的基因表达水平。