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

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

doi:10.1016/j.molcel.2024.04.011

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

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^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2320-2336.e6
Journal	Molecular cell
Volume	84
Issue number	12
DOIs	https://doi.org/10.1016/j.molcel.2024.04.011
State	Published - Jun 20 2024

Funding

This project is supported in part by NIH grants R01GM125632 , R01GM138407 , R01HL148338 , and R01HL133254 to K.C.; R01CA208257 and R01CA256741 to Q.C.; R01HL155632 to L.Z.; U.S. Department of Defense grants W81XWH-17-1-0357 , W81XWH-19-1-0563 , and W81XWH-20-1-0504 to Q.C. and HT9425-23-1-0661 to Y.Y.; and Prostate SPORE P50CA180995 Development Research Program and the Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital to Q.C. The nanopore RNA-seq was done at Northwestern University NUseq facility core with the support of NIH grant ( 1S10OD025120 ). Proteomics services were performed by the Northwestern Proteomics Core Facility and were generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center, instrumentation award ( S10OD025194 ) from NIH Office of Director , and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569 .

Keywords

2′-O-methylation
CPSF7
FBL
RNA stability
alternative polyadenylation
epitranscriptomics
mRNA modification
machine learning
nanopore
prostate cancer

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2024.04.011

Cite this

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title = "2′-O-methylation at internal sites on mRNA promotes mRNA stability",

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.",

keywords = "2′-O-methylation, CPSF7, FBL, RNA stability, alternative polyadenylation, epitranscriptomics, mRNA modification, machine learning, nanopore, prostate cancer",

author = "Yanqiang Li and Yang Yi and Xinlei Gao and Xin Wang and Dongyu Zhao and Rui Wang and Zhang, \{Li Sheng\} and Boyang Gao and Yadong Zhang and Lili Zhang and Qi Cao and Kaifu Chen",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

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day = "20",

doi = "10.1016/j.molcel.2024.04.011",

language = "English (US)",

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T1 - 2′-O-methylation at internal sites on mRNA promotes mRNA stability

AU - Li, Yanqiang

AU - Yi, Yang

AU - Gao, Xinlei

AU - Wang, Xin

AU - Zhao, Dongyu

AU - Wang, Rui

AU - Zhang, Li Sheng

AU - Gao, Boyang

AU - Zhang, Yadong

AU - Zhang, Lili

AU - Cao, Qi

AU - Chen, Kaifu

PY - 2024/6/20

Y1 - 2024/6/20

N2 - 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.

AB - 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.

KW - 2′-O-methylation

KW - CPSF7

KW - FBL

KW - RNA stability

KW - alternative polyadenylation

KW - epitranscriptomics

KW - mRNA modification

KW - machine learning

KW - nanopore

KW - prostate cancer

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JO - Molecular cell

JF - Molecular cell

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ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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