Acetylation of Cytidine in mRNA Promotes Translation Efficiency

Daniel Arango; David Sturgill; Najwa Alhusaini; Allissa A. Dillman; Thomas J. Sweet; Gavin Hanson; Masaki Hosogane; Wilson R. Sinclair; Kyster K. Nanan; Mariana D. Mandler; Stephen D. Fox; Thomas T. Zengeya; Thorkell Andresson; Jordan L. Meier; Jeffery Coller; Shalini Oberdoerffer

doi:10.1016/j.cell.2018.10.030

Acetylation of Cytidine in mRNA Promotes Translation Efficiency

Daniel Arango, David Sturgill, Najwa Alhusaini, Allissa A. Dillman, Thomas J. Sweet, Gavin Hanson, Masaki Hosogane, Wilson R. Sinclair, Kyster K. Nanan, Mariana D. Mandler, Stephen D. Fox, Thomas T. Zengeya, Thorkell Andresson, Jordan L. Meier, Jeffery Coller, Shalini Oberdoerffer^*

^*Corresponding author for this work

Pharmacology

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

494 Scopus citations

Abstract

Generation of the “epitranscriptome” through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation. Analysis of mRNA half-lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation.

Original language	English (US)
Pages (from-to)	1872-1886.e24
Journal	Cell
Volume	175
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2018.10.030
State	Published - Dec 13 2018

Funding

We thank the members of the Center for Cancer Research Sequencing Facility at the National Cancer Institute (Frederick, MD) for providing Illumina sequencing services. We thank Dr. Lin Qishan from the Mass Spectrometry Center at the RNA Institute SUNY-Albany (Albany, NY) for providing LC-MS/MS services. This study utilized the Biowulf Linux cluster at the NIH, Bethesda, MD (https://hpc.nih.gov). This work is supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. Support for J.C. was provided by the NIH (GM118018, GM125086). We thank the members of the Center for Cancer Research Sequencing Facility at the National Cancer Institute (Frederick, MD) for providing Illumina sequencing services. We thank Dr. Lin Qishan from the Mass Spectrometry Center at the RNA Institute SUNY-Albany (Albany, NY) for providing LC-MS/MS services. This study utilized the Biowulf Linux cluster at the NIH, Bethesda, MD ( https://hpc.nih.gov ). This work is supported by the Intramural Research Program of the National Institutes of Health (NIH) , NCI , Center for Cancer Research . Support for J.C. was provided by the NIH ( GM118018 , GM125086 ).

Keywords

N4-acetylcytidine
NAT10
epitranscriptome
mRNA stability
mRNA translation

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2018.10.030

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Arango, D., Sturgill, D., Alhusaini, N., Dillman, A. A., Sweet, T. J., Hanson, G., Hosogane, M., Sinclair, W. R., Nanan, K. K., Mandler, M. D., Fox, S. D., Zengeya, T. T., Andresson, T., Meier, J. L., Coller, J., & Oberdoerffer, S. (2018). Acetylation of Cytidine in mRNA Promotes Translation Efficiency. Cell, 175(7), 1872-1886.e24. https://doi.org/10.1016/j.cell.2018.10.030

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title = "Acetylation of Cytidine in mRNA Promotes Translation Efficiency",

abstract = "Generation of the “epitranscriptome” through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation. Analysis of mRNA half-lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation.",

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doi = "10.1016/j.cell.2018.10.030",

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T1 - Acetylation of Cytidine in mRNA Promotes Translation Efficiency

AU - Arango, Daniel

AU - Sturgill, David

AU - Alhusaini, Najwa

AU - Dillman, Allissa A.

AU - Sweet, Thomas J.

AU - Hanson, Gavin

AU - Hosogane, Masaki

AU - Sinclair, Wilson R.

AU - Nanan, Kyster K.

AU - Mandler, Mariana D.

AU - Fox, Stephen D.

AU - Zengeya, Thomas T.

AU - Andresson, Thorkell

AU - Meier, Jordan L.

AU - Coller, Jeffery

AU - Oberdoerffer, Shalini

PY - 2018/12/13

Y1 - 2018/12/13

N2 - Generation of the “epitranscriptome” through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation. Analysis of mRNA half-lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation.

AB - Generation of the “epitranscriptome” through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation. Analysis of mRNA half-lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation.

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Acetylation of Cytidine in mRNA Promotes Translation Efficiency

Abstract

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