YTHDF1 suppresses innate immune responses by promoting induction of A-to-I RNA editing

In this study, we show that the m6A modification promotes translation of the ADAR1 transcript, which encodes an A-to-I RNA editing enzyme, in response to interferon stimulation. We reveal that this translation upregulation is mediated by the YTHDF1-dependent pathway; YTHDF1 is a reader protein that can preferentially bind m6A-modified transcripts and promote translation. Knockdown of YTHDF1 reduces the overall levels of interferon-induced A-to-I RNA editing, which consequently activates dsRNA-sensing pathway and increased expression of various interferon-stimulated genes. These RNA-seq experiments investigate the effect of YTHDF1 knockdown on the interferon-treated A172 cell transcriptome. Overall design: mRNA profiles of A172 glioblastoma cells with IFN treatment and YTHDF1 knockdown were generated by deep sequencing, in triplicate.

本研究表明，N6-甲基腺苷（m6A）修饰可在干扰素刺激下，促进编码A-to-I RNA编辑酶的ADAR1转录本的翻译过程。本研究揭示，该翻译上调过程由依赖YTH N6-甲基腺苷RNA结合蛋白1（YTHDF1）的通路介导；YTHDF1作为一类m6A阅读蛋白，可优先结合带有m6A修饰的转录本并促进其翻译。敲低YTHDF1会降低干扰素诱导的A-to-I RNA编辑整体水平，进而激活双链RNA（dsRNA）感知通路，并上调多种干扰素刺激基因的表达。本项RNA测序（RNA-seq）实验旨在探究YTHDF1敲低对经干扰素处理的A172细胞转录组的影响。整体实验设计：通过深度测序构建了经干扰素（IFN）处理并敲低YTHDF1的A172胶质母细胞瘤细胞的mRNA表达谱，实验共设置三次生物学重复。