Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD⁺-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD⁺ consumption. The resultant accumulation of the NAD⁺ precursor NMN allows for maintenance of mitochondrial NAD⁺ pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD⁺ consumption and establishing a buffer of NAD⁺ precursors in differentiated cells.

中文翻译：

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MacroH2A1.1 通过限制核 NAD+ 消耗来调节线粒体呼吸


组蛋白变体是真核染色质的结构成分，可以取代核小体中的复制偶联组蛋白。组蛋白变体 MacroH2A1.1 包含能够结合 NAD ⁺衍生代谢物的大结构域。在这里，我们报告，macroH2A1.1 在成肌分化过程中通过选择性剪接的转换被快速诱导，并且缺乏 MacroH2A1.1 的肌管线粒体呼吸能力存在缺陷。我们发现代谢物结合大结构域对于维持最佳线粒体功能至关重要，但对于基因调控来说却是可有可无的。通过直接结合，macroH2A1.1 抑制基础聚 ADP 核糖聚合酶 1 (PARP-1) 活性，从而减少核 NAD ⁺消耗。 NAD ⁺前体 NMN 的积累可以维持对呼吸至关重要的线粒体 NAD ⁺库。我们的数据表明，含有 MacroH2A1.1 的染色质通过限制核 NAD ⁺消耗并在分化细胞中建立 NAD ⁺前体缓冲液来调节线粒体呼吸。