Loss of macroH2A1.1 causes kidney abnormalities secondary to a change in nutrient metabolization

Histone variants with metabolite-binding macrodomains provide a poorly understood link between chromatin composition and metabolism. To address their contribution to physiological health, we have generated and analyzed mice exclusively lacking the histone variants macroH2A1.1, macroH2A1.2, or macroH2A2. We identify several histopathological changes in the kidney as a novel isoform-specific phenotype of complete macroH2A1.1 loss. Kidney alterations, such as increased cast formation or the presence of interstitial inflammatory infiltrates, were not associated with organ-intrinsic changes in gene expression but strongly correlated with a shift in nutrient metabolization. Reduced lipid oxidation and increased glycolysis were found in both male and female mice with isoform-specific macroH2A1.1 loss. However, male macroH2A1.1 knock-out mice had a better glucose tolerance accompanied by changes in the expression of metabolic genes in the liver. Forcing mice to metabolize fat by replacing chow diet with a ketogenic diet overrode the macroH2A1.1-dependent metabolic phenotype and prevented the appearance of kidney abnormalities. Taken together, our results indicate that macroH2A1.1 controls nutrient metabolization and links macroH2A1.1 levels to secondary changes in the kidney.