Dynamic m6 A mRNA methylation directs translational control of heat shock response

Abstract

The most abundant mRNA post-transcriptional modification is N6-methyladenosine (m6 A), which has broad roles in RNA biology. In mammalian cells, the asymmetric distribution of m6 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 m6 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 m6 A 'reader'. Upon heat shock stress, the nuclear YTHDF2 preserves 5′UTR methylation of stress-induced transcripts by limiting the m6 A 'eraser' FTO from demethylation. Remarkably, the increased 5′UTR methylation in the form of m6 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 m6 A 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 m6 A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.