Epigenetic alterations facilitate transcriptional and translational programs in hypoxia
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.
Authors
- Laìa Masvidal (ORCID: https://orcid.org/0000-0002-0460-3058)
- Kristofferson Tandoc (ORCID: https://orcid.org/0000-0002-8630-2768)
- Ivan Topisirović
- Predrag Jovanovic (ORCID: https://orcid.org/0000-0002-0090-0047)
- David Papadopoli
- Laura Lee (ORCID: https://orcid.org/0000-0002-7974-6803)
- Tyler T. Cooper (ORCID: https://orcid.org/0000-0003-4662-8816)
- Julia Vassalakis (ORCID: https://orcid.org/0009-0000-1261-3638)
- Lynne‐Marie Postovit (ORCID: https://orcid.org/0000-0002-8088-4197)
- Gilles Lajoie (ORCID: https://orcid.org/0000-0002-3989-5134)
- Kathleen Watt (ORCID: https://orcid.org/0000-0001-6642-9756)
- Michael Jewer
- Krzysztof J. Szkop (ORCID: https://orcid.org/0000-0001-7845-2945)
- Howard K. Plummer
- Ola Larsson (ORCID: https://orcid.org/0000-0003-1412-1308)
- Bianca Dauber (ORCID: https://orcid.org/0009-0006-6755-3840)
- Ranveer Palia
- Shan Chen (ORCID: https://orcid.org/0000-0002-6177-5980)
Institutions
- Western University (CA)
- University of Alberta (CA)
- Queen's University (CA)
- Science for Life Laboratory (SE)
- Jewish General Hospital (CA)
- Karolinska Institutet (SE)
- McGill University (CA)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-10-16
- DOI
- https://doi.org/10.1038/s41556-025-01786-8
- Citations
- 3
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 2.42