A-to-I RNA editing is a widespread epitranscriptomic phenomenon leading to the conversion of adenosines to inosines, which are primarily interpreted as guanosines by cellular machines. Consequently, A-to-I editing can alter splicing or lead to recoding of transcripts. As misregulation of editing can cause a variety of human diseases, A-to-I editing requires tight regulation of the extent of deamination, particularly in protein-coding regions. The bulk of A-to-I editing occurs cotranscriptionally. Thus, we studied A-to-I editing regulation in the context of transcription and pre-mRNA processing. We show that stimulation of transcription impacts editing levels. Activation of the transcription factor MYC leads to an up-regulation of A-to-I editing, particularly in transcripts that are suppressed upon MYC activation. Moreover, low pre-mRNA synthesis rates and low pre-mRNA expression levels support high levels of editing. We also show that editing levels greatly differ between nascent pre-mRNA and mRNA in a cellular system, as well as in mouse tissues. Editing levels can increase or decrease from pre-mRNA to mRNA and can vary across editing targets and across tissues, showing that pre-mRNA processing is an important layer of editing regulation. Several lines of evidence suggest that the differences emerge during pre-mRNA splicing. Moreover, actinomycin D treatment of primary neuronal cells and editing level analysis suggests that regulation of editing levels also depends on transcription.

中文翻译：

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RNA Pol II 依赖的转录效率微调 A 到 I 编辑水平

A-to-I RNA 编辑是一种广泛存在的表观转录组现象，可导致腺苷转化为肌苷，而肌苷主要被细胞机器解释为鸟苷。因此，A-to-I 编辑可以改变剪接或导致转录本重新编码。由于编辑的错误调控可能导致多种人类疾病，因此 A 到 I 编辑需要严格调控脱氨基的程度，特别是在蛋白质编码区域。大部分 A 到 I 编辑是在共转录过程中发生的。因此，我们在转录和前 mRNA 加工的背景下研究了 A 到 I 的编辑调控。我们证明转录的刺激会影响编辑水平。转录因子 MYC 的激活会导致 A 到 I 编辑的上调，特别是在 MYC 激活时受到抑制的转录本中。此外，低前体 mRNA 合成率和低前体 mRNA 表达水平支持高水平的编辑。我们还表明，细胞系统以及小鼠组织中新生前 mRNA 和 mRNA 的编辑水平存在很大差异。编辑水平可以从前 mRNA 到 mRNA 增加或减少，并且可以根据编辑目标和组织的不同而变化，这表明前 mRNA 加工是编辑调控的重要层。多项证据表明差异是在 mRNA 前体剪接过程中出现的。此外，放线菌素 D 对原代神经元细胞的处理和编辑水平分析表明，编辑水平的调节也取决于转录。