Letter | Published:

Dynamic m6A mRNA methylation directs translational control of heat shock response

Nature volume 526, pages 591594 (22 October 2015) | Download Citation

Abstract

The most abundant mRNA post-transcriptional modification is N6-methyladenosine (m6A), which has broad roles in RNA biology1,2,3,4,5. In mammalian cells, the asymmetric distribution of m6A along mRNAs results in relatively less methylation in the 5′ untranslated region (5′UTR) compared to other regions6,7. However, whether and how 5′UTR methylation is regulated is poorly understood. Despite the crucial role of the 5′UTR in translation initiation, very little is known about whether m6A modification influences mRNA translation. Here we show that in response to heat shock stress, certain adenosines within the 5′UTR of newly transcribed mRNAs are preferentially methylated. We find that the dynamic 5′UTR methylation is a result of stress-induced nuclear localization of YTHDF2, a well-characterized m6A ‘reader’. Upon heat shock stress, the nuclear YTHDF2 preserves 5′UTR methylation of stress-induced transcripts by limiting the m6A ‘eraser’ FTO from demethylation. Remarkably, the increased 5′UTR methylation in the form of m6A promotes cap-independent translation initiation, providing a mechanism for selective mRNA translation under heat shock stress. Using Hsp70 mRNA as an example, we demonstrate that a single m6A modification site in the 5′UTR enables translation initiation independent of the 5′ end N7-methylguanosine cap. The elucidation of the dynamic features of 5′UTR methylation and its critical role in cap-independent translation not only expands the breadth of physiological roles of m6A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.

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Sequence Read Archive

Data deposits

Sequencing data have been deposited at NCBI Sequence Read Archive under accession number SRA280261.

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Acknowledgements

We would like to thank Qian laboratory members for helpful discussions and Cornell University Life Sciences Core Laboratory Center for performing deep sequencing. This work was supported by grants from the US National Institutes of Health DP2 OD006449 and R01AG042400 (to S.-B.Q.) and NIDA DA037150 (to S.R.J.) and the US Department of Defense (W81XWH-14-1-0068) (to S.-B.Q.).

Author information

Affiliations

  1. Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA

    • Jun Zhou
    • , Ji Wan
    • , Xiangwei Gao
    • , Xingqian Zhang
    •  & Shu-Bing Qian
  2. Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York City, New York 10065, USA

    • Samie R. Jaffrey

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Contributions

J.Z. and S.-B.Q. conceived the project. J.Z. performed most experiments. J.W. analysed the sequencing data. X.G. performed Ribo-seq. X.Z. assisted heat shock assays. S.R.J. helped with original FTO ideas. S.-B.Q. wrote the manuscript. All authors discussed the results and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shu-Bing Qian.

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https://doi.org/10.1038/nature15377

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