Dynamic m(6)A mRNA Methylation Directs Translational Control of Heat Shock Response

Nature. 2015 Oct 22;526(7574):591-4. doi: 10.1038/nature15377. Epub 2015 Oct 12.

Abstract

The most abundant mRNA post-transcriptional modification is N(6)-methyladenosine (m(6)A), which has broad roles in RNA biology. In mammalian cells, the asymmetric distribution of m(6)A along mRNAs results in relatively less methylation in the 5' untranslated region (5'UTR) compared to other regions. 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 m(6)A 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 m(6)A 'reader'. Upon heat shock stress, the nuclear YTHDF2 preserves 5'UTR methylation of stress-induced transcripts by limiting the m(6)A 'eraser' FTO from demethylation. Remarkably, the increased 5'UTR methylation in the form of m(6)A 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 m(6)A modification site in the 5'UTR enables translation initiation independent of the 5' end N(7)-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 m(6)A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation*
  • HSP70 Heat-Shock Proteins / genetics
  • Heat-Shock Response* / genetics
  • Methylation*
  • Mice
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / metabolism
  • Oxo-Acid-Lyases / antagonists & inhibitors
  • Oxo-Acid-Lyases / metabolism
  • Peptide Chain Initiation, Translational*
  • RNA Caps / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / metabolism
  • Transcription, Genetic / genetics

Substances

  • 5' Untranslated Regions
  • HSP70 Heat-Shock Proteins
  • RNA Caps
  • RNA, Messenger
  • RNA-Binding Proteins
  • YTHDF2 protein, mouse
  • N(6)-methyladenosine
  • Mixed Function Oxygenases
  • FTO protein, mouse
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Oxo-Acid-Lyases
  • Adenosine

Associated data

  • SRA/SRA280261