Histone H3K4me3 breadth in hypoxia reveals endometrial core functions and stress adaptation linked to endometriosis
Kalle T. Rytkönen,
Thomas Faux,
Mehrad Mahmoudian,
Taija Heinosalo,
Mauris C. Nnamani,
Antti Perheentupa,
Matti Poutanen,
Laura L. Elo,
Günter P. Wagner
Affiliations
Kalle T. Rytkönen
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Yale Systems Biology Institute, West Haven, CT 06516, USA; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Kiinamyllynkatu 10, 20014 Turku, Finland; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA; Corresponding author
Thomas Faux
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland
Mehrad Mahmoudian
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Kiinamyllynkatu 10, 20014 Turku, Finland
Taija Heinosalo
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Kiinamyllynkatu 10, 20014 Turku, Finland
Mauris C. Nnamani
Yale Systems Biology Institute, West Haven, CT 06516, USA; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA
Antti Perheentupa
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Kiinamyllynkatu 10, 20014 Turku, Finland; Department of Obstetrics and Gynecology, Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
Matti Poutanen
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Kiinamyllynkatu 10, 20014 Turku, Finland
Laura L. Elo
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20014 Turku, Finland
Günter P. Wagner
Yale Systems Biology Institute, West Haven, CT 06516, USA; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Medical School, New Haven, CT 06510, USA; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA; Corresponding author
Summary: Trimethylation of histone H3 at lysine 4 (H3K4me3) is a marker of active promoters. Broad H3K4me3 promoter domains have been associated with cell type identity, but H3K4me3 dynamics upon cellular stress have not been well characterized. We assessed this by exposing endometrial stromal cells to hypoxia, which is a major cellular stress condition. We observed that hypoxia modifies the existing H3K4me3 marks and that promoter H3K4me3 breadth rather than height correlates with transcription. Broad H3K4me3 domains mark genes for endometrial core functions and are maintained or selectively extended upon hypoxia. Hypoxic extension of H3K4me3 breadth associates with stress adaptation genes relevant for the survival of endometrial cells including transcription factor KLF4, for which we found increased protein expression in the stroma of endometriosis lesions. These results substantiate the view on broad H3K4me3 as a marker of cell identity genes and reveal participation of H3K4me3 extension in cellular stress adaptation.
