Dynamic m(6)A mRNA methylation directs translational control of heat shock response.

Abstract

The most abundant mRNA post-transcriptional modification is N6-methyladenosine (m6A) that has broad roles in RNA biology1-5. In mammalian cells, the asymmetric distribution of m6A along mRNAs leaves 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 whether m6A modification influences mRNA translation. Here we show that in response to heat shock stress, m6A is preferentially deposited to the 5′UTR of newly transcribed mRNAs. We found 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 site m6A modification in the 5′UTR enables translation initiation independent of the 5′ end m7G cap. The elucidation of the dynamic feature 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.