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.具有代谢物结合宏结构域（macrodomain）的组蛋白变体（histone variants），为染色质组成与代谢过程搭建了一条尚未被充分阐释的关联纽带。为阐明此类变体对生理健康的调控作用，我们构建并分析了三类特异性敲除组蛋白变体macroH2A1.1、macroH2A1.2或macroH2A2的小鼠模型。我们发现，完全缺失macroH2A1.1会引发肾脏出现多种组织病理学改变，这是一种全新的亚型特异性表型。肾脏出现的异常改变（如管型增多或间质炎性浸润），并未伴随肾脏自身的基因表达变化，但与营养代谢模式的显著改变密切相关。在macroH2A1.1亚型特异性缺失的雌雄小鼠中，均观察到脂质氧化水平降低、糖酵解活性增强的现象。但雄性macroH2A1.1敲除小鼠的葡萄糖耐受能力有所提升，同时肝脏内代谢相关基因的表达模式发生改变。通过用生酮饮食（ketogenic diet）替换普通标准饲料（chow diet），迫使小鼠以脂肪作为主要代谢底物，可抵消macroH2A1.1依赖型代谢表型，并阻止肾脏异常的发生。综上，本研究结果表明，macroH2A1.1可调控营养代谢过程，并将其自身表达水平与肾脏的继发性改变相关联。