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Sci Rep. 2018 Feb 13;8(1):2940. doi: 10.1038/s41598-018-21372-3.

Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila.

Author information

1
Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
2
Department of Molecular Cardiology and Epigenetics, University of Heidelberg, Heidelberg, Germany.
3
DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
4
Clinical Sensoring and Monitoring, Anesthesiology and Intensive Care Medicine, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
5
Max Planck Insitute of Molecular Biology and Genetics, Pfotenhauerstr. 108, 01307, Dresden, Germany.
6
Comprehensive Heart Failure Center, University of Würzburg, Versbacher Strasse 9, 97078, Wuerzburg, Germany.
7
West German Heart and Vascular Center Essen, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.
8
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal; Departments of Medicine and Pharmacology and Therapeutics, McGill University, Montreal, Canada.
9
Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, Essen, Germany.
10
Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Strasse 11, 44139, Dortmund, Germany.
11
Institute of Pharmacology and Toxicology, University of Wuerzburg, Versbacher Strasse 9, 97078, Wuerzburg, Germany.
12
Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany. Silvio.Weber@tu-dresden.de.
13
Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany. Ali.El-Armouche@tu-dresden.de.

Abstract

Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.

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