Loss of histone macroH2A1.1 causes kidney abnormalities secondary to a change in nutrient metabolization
Year: 2025
Type: article
Abstract: Histone variants with metabolite-binding macrodomains provide a poorly understood link between chromatin composition and metabolism. To address their contribution to physiological health, we generated and analyzed mice individually lacking the histone variants macroH2A1.1, macroH2A1.2, or macroH2A2. We identified several histopathologic changes in the kidney as isoform-specific phenotype of complete macroH2A1.1 loss affecting male and female animals. Kidney alterations were barely associated with organ-intrinsic gene expression changes but strongly correlated with a systemic shift in nutrient metabolization and alterations in NAD + (nicotinamide adenine dinucleotide, oxidized form) metabolism. Reduced lipid oxidation and increased glycolysis were found in male and female mice lacking macroH2A1.1 but not macroH2A1.2 or macroH2A2. Male macroH2A1.1-deficient mice also had better glucose tolerance and altered hepatic gene expression. Replacing chow by ketogenic diet overrode the macroH2A1.1-dependent metabolic phenotype and prevented kidney abnormalities. Together, our results indicate that macroH2A1.1 controls nutrient metabolization and links macroH2A1.1 levels to secondary changes in the kidney.
Source: Science Advances
Authors: René Winkler, Gemma Comas-Armangué, David Corujo, Adrián Sanz-Moreno, Julia Calzada-Wack, Shubhra Ashish Bhattacharya, Birgit Rathkolb, Nathalia Romanelli Vicente Dragano, Colina X. Qiao, Valentina Chiodi, Dan Filipescu, Dylan H. Park, Maria Rosaria Domenici, Valentina Kirigin Callaú, Raffaele Gerlini, Jan Rozman, Tanja Klein-Rodewald, Antonio Aguilar-Pimentel, Lore Becker, Claudia Seisenberger, Susan Marschall, Helmut Fuchs, Valérie Gailus-Durner, Emily Bernstein, Manlio Vinciguerra, Philipp Oberdoerffer, Martin Hrabě de Angelis, Raffaele Teperino, Marcus Buschbeck
Institutions: Josep Carreras Leukaemia Research Institute, Helmholtz Munich, German Center for Diabetes Research, Universitat Autònoma de Barcelona, Ludwig-Maximilians-Universität München, Johns Hopkins University, Johns Hopkins Medicine, Istituto Superiore di Sanità, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Medical University of Varna, Liverpool John Moores University, Technical University of Munich, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W4415525554