Epigenetic coordination of transcriptional and translational programs in hypoxia

Abstract

Adaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene expression programs. Here, we quantified hypoxia-dependent transcriptomes, epigenomes, and translatomes in T47D breast cancer cells and H9 human embryonic stem cells. This revealed pervasive changes in transcription start site (TSS) selection associated with nucleosome repositioning and alterations in H3K4me3 distribution. Importantly, hypoxia-associated TSS switching was induced or reversed via pharmacological modulation of H3K4me3 in the absence of hypoxia, defining a role for H3K4me3 in TSS selection independent of HIF1-transcriptional programs. By remodelling 5UTRs, TSS switching selectively alters protein synthesis, including enhanced translation of mRNAs encoding pyruvate dehydrogenase kinase 1 (PDK1) that is essential for the metabolic adaptation to hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation during hypoxia driven by epigenetic reprogramming of the 5UTRome.