2′-O-methylation at internal sites on mRNA promotes mRNA stability

• DOI: 10.1016/j.molcel.2024.04.011
• Publication Date: 2024-06-20T14:41:48Z
• Authors: Yanqiang Li; Yang Yi; Xinlei Gao; Xin Wang; Dongyu Zhao; Rui Wang; Li-Sheng Zhang; Boyang Gao; Yadong Zhang; Lili Zhang; Qi Cao; Kaifu Chen
• Keywords: Gene Expression Regulation, Neoplastic; Machine Learning; Nanopore Sequencing; RNA Stability; 610; Humans; RNA, Messenger; RNA Processing, Post-Transcriptional; Transcriptome; Methylation; 3' Untranslated Regions

2'-O-methylation (Nm) is a prominent RNA modification well known in noncoding RNAs and more recently also found at many mRNA internal sites. However, their function and base-resolution stoichiometry remain underexplored. Here, we investigate the transcriptome-wide effect of internal site Nm on mRNA stability. Combining nanopore sequencing with our developed machine learning method, NanoNm, we identify thousands of Nm sites on mRNAs with a single-base resolution. We observe a positive effect of FBL-mediated Nm modification on mRNA stability and expression level. Elevated FBL expression in cancer cells is associated with increased expression levels for 2'-O-methylated mRNAs of cancer pathways, implying the role of FBL in post-transcriptional regulation. Lastly, we find that FBL-mediated 2'-O-methylation connects to widespread 3' UTR shortening, a mechanism that globally increases RNA stability. Collectively, we demonstrate that FBL-mediated Nm modifications at mRNA internal sites regulate gene expression by enhancing mRNA stability.