Epigenetic coordination of transcriptional and translational programs in hypoxia

Adaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene regulation. Here, we quantified hypoxia-dependent transcriptomes, epigenomes and translatomes in T47D breast cancer cells and H9 human embryonic stem cells. This revealed alterations in H3K4me3 associating with pervasive changes in transcription start site (TSS) selection leading to remodeling of 5’UTRs, which act as critical hubs regulating translation, and a concomitant reshaping of translational landscapes. Moreover, modulating H3K4me3 could both recapitulate and block a subset of hypoxia-induced TSS switching, defining a role for H3K4me3 in TSS selection, independently of HIF1-dependent transcriptional mechanisms. While TSS switching is coordinated with the integrated stress response (ISR) and mTOR-guided translational reprogramming, it also acts independently to regulate translation in hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation driven by epigenetic reprogramming of the 5’UTRome, which is orchestrated with other hypoxia-triggered adaptive mechanisms.