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Altered m6A modification of specific cellular transcripts affects Flaviviridae infection

View ORCID ProfileNandan S. Gokhale, Alexa B.R. McIntyre, Melissa D. Mattocks, Christopher L. Holley, Helen M. Lazear, Christopher E. Mason, Stacy M. Horner
doi: https://doi.org/10.1101/670984
Nandan S. Gokhale
1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27705, USA
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  • ORCID record for Nandan S. Gokhale
Alexa B.R. McIntyre
3Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
4Tri-Institutional Program in Computational Biology and Medicine, New York, NC 10065, USA
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Melissa D. Mattocks
5Department of Microbiology and Immunology, University of North Carolina – Chapel Hill, Chapel Hill, NC 27599, USA
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Christopher L. Holley
1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27705, USA
2Department of Medicine, Duke University Medical Center, Durham, NC 27705, USA
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Helen M. Lazear
5Department of Microbiology and Immunology, University of North Carolina – Chapel Hill, Chapel Hill, NC 27599, USA
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Christopher E. Mason
3Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
6The HRH Prince Alwaleed Bin Talal Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
7The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, 10065, USA
8The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
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  • For correspondence: stacy.horner@duke.edu chm2042@med.cornell.edu
Stacy M. Horner
1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27705, USA
2Department of Medicine, Duke University Medical Center, Durham, NC 27705, USA
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  • For correspondence: stacy.horner@duke.edu chm2042@med.cornell.edu
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Summary

The RNA modification N6-methyladenosine (m6A) can modulate mRNA fate and thus affect many biological processes. We analyzed m6A modification across the transcriptome following infection by dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and hepatitis C virus (HCV). We found that infection by these viruses in the Flaviviridae family alters m6A modification of specific cellular transcripts, including RIOK3 and CIRBP. During viral infection, the addition of m6A to RIOK3 promotes its translation, while loss of m6A in CIRBP promotes alternative splicing. Importantly, we found that activation of innate immune sensing or the endoplasmic reticulum (ER) stress response by viral infection contributes to the changes in m6A modification in RIOK3 and CIRBP, respectively. Further, several transcripts with infection-altered m6A profiles, including RIOK3 and CIRBP, encode proteins that influence DENV, ZIKV, and HCV infection. Overall, this work reveals that cellular signaling pathways activated during viral infection lead to alterations in m6A modification of host mRNAs to regulate infection.

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Posted June 13, 2019.
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Altered m6A modification of specific cellular transcripts affects Flaviviridae infection
Nandan S. Gokhale, Alexa B.R. McIntyre, Melissa D. Mattocks, Christopher L. Holley, Helen M. Lazear, Christopher E. Mason, Stacy M. Horner
bioRxiv 670984; doi: https://doi.org/10.1101/670984
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Altered m6A modification of specific cellular transcripts affects Flaviviridae infection
Nandan S. Gokhale, Alexa B.R. McIntyre, Melissa D. Mattocks, Christopher L. Holley, Helen M. Lazear, Christopher E. Mason, Stacy M. Horner
bioRxiv 670984; doi: https://doi.org/10.1101/670984

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