1. 2′-O-methylation at internal sites on mRNA promotes mRNA stability.
- Author
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Li, Yanqiang, Yi, Yang, Gao, Xinlei, Wang, Xin, Zhao, Dongyu, Wang, Rui, Zhang, Li-Sheng, Gao, Boyang, Zhang, Yadong, Zhang, Lili, Cao, Qi, and Chen, Kaifu
- Subjects
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RNA modification & restriction , *GENE expression , *MESSENGER RNA , *NON-coding RNA , *RNA sequencing - Abstract
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. • Widespread 2′-O-methylation (Nm) at mRNA internal sites promotes mRNA stability • De novo detection and measurement of Nm by nanopore RNA-seq and machine learning • FBL deficiency decreased Nm, stability, and expression level of mRNAs in PCa • Nm is linked to alternative polyadenylation, which leads to 3′ UTR shortening Li et al. develop a machine learning approach to measure the stoichiometry of 2′-O-methylation at internal sites of mRNA using nanopore RNA sequencing data. FBL-mediated Nm modifications, when connected to widespread shortening of the 3′ UTR, regulate gene expression by enhancing mRNA stability. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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