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Watt K, Dauber B, Szkop KJ, Lee L, Jovanovic P, Chen S, Palia R, Vassalakis JA, Cooper TT, Papadopoli D, Masvidal L, Jewer M, Tandoc K, Plummer H, Lajoie GA, Topisirovic I, Larsson O, Postovit LM
Nat Cell Biol - (-) - [2025-10-16; online 2025-10-16]
Adaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene expression programs. Here, by quantifying hypoxia-dependent transcriptomes, epigenomes and translatomes in T47D breast cancer cells and H9 human embryonic stem cells, we show pervasive changes in transcription start site (TSS) selection associated with nucleosome repositioning and alterations in H3K4me3 distribution. Notably, 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 5'UTRs, TSS switching selectively alters protein synthesis, including enhanced translation of messenger RNAs encoding pyruvate dehydrogenase kinase 1, which is essential for metabolic adaptation to hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation during hypoxia driven by epigenetic reprogramming of the 5'UTRome.
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 41102449
DOI 10.1038/s41556-025-01786-8
Crossref 10.1038/s41556-025-01786-8
pii: 10.1038/s41556-025-01786-8