Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
Science. 2020 Jan 31;367(6477):580-586. doi: 10.1126/science.aay6018. Epub 2020 Jan 16.
-methyladenosine (mA) regulates stability and translation of messenger RNA (mRNA) in various biological processes. In this work, we show that knockout of the mA writer or the nuclear reader in mouse embryonic stem cells increases chromatin accessibility and activates transcription in an mA-dependent manner. We found that METTL3 deposits mA modifications on chromosome-associated regulatory RNAs (carRNAs), including promoter-associated RNAs, enhancer RNAs, and repeat RNAs. YTHDC1 facilitates the decay of a subset of these mA-modified RNAs, especially elements of the long interspersed element-1 family, through the nuclear exosome targeting-mediated nuclear degradation. Reducing mA methylation by METTL3 depletion or site-specific mA demethylation of selected carRNAs elevates the levels of carRNAs and promotes open chromatin state and downstream transcription. Collectively, our results reveal that mA on carRNAs can globally tune chromatin state and transcription.
-甲基腺苷（mA）在各种生物过程中调节信使 RNA（mRNA）的稳定性和翻译。在这项工作中，我们表明，在小鼠胚胎干细胞中敲除 mA 书写器 或核读取器 以 mA 依赖的方式增加染色质可及性并激活转录。我们发现，METTL3 将 mA 修饰沉积在染色体相关的调节 RNA（carRNA）上，包括启动子相关 RNA、增强子 RNA 和重复 RNA。YTHDC1 通过核外切体靶向介导的核降解促进这些 mA 修饰 RNA 的一部分（特别是长散布元件 1 家族的元件）的降解。通过 METTL3 耗竭减少 mA 甲基化或对选定的 carRNA 进行特异性 mA 去甲基化可提高 carRNA 的水平，并促进开放染色质状态和下游转录。总之，我们的结果表明，carRNA 上的 mA 可以全局调节染色质状态和转录。
