Epigenetic coordination of transcriptional and translational programs in hypoxia

Adaptation to stresses entails coordination of transcriptional and post-transcriptional gene regulation, but the mechanisms remain largely unknown. We interrogated the effects of hypoxia on transcriptomes, epigenomes and translatomes of T47D breast cancer cells and H9 human embryonic stem cells. This revealed hypoxia-induced alterations in H3K4me3 associating with pervasive changes in transcription start site (TSS) selection, leading to 5'UTR remodeling and a concomitant reshaping of translational landscapes. Importantly, this epigenetically driven reprogramming of translation is distinct from HIF1-dependent transcriptional mechanisms, and TSS switching appears to occur independently of alterations in transcript abundance. 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. Moreover, comparable TSS switching was observed following H3K4me3 accumulation in the absence of hypoxia, pinpointing H3K4me3 as underlying TSS selection. 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.