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 ⁺消耗量来调节线粒体呼吸

组蛋白变体是真核染色质的结构成分，可以替代核小体中复制偶联的组蛋白。组蛋白变体macroH2A1.1包含一个能够结合NAD ⁺衍生代谢产物的宏结构域。在这里我们报告说，macroH2A1.1在成肌分化过程中通过选择性剪接的切换而被快速诱导，而缺少macroH2A1.1的肌管在线粒体呼吸能力方面存在缺陷。我们发现代谢物结合大域对于持续的最佳线粒体功能是必不可少的，但对于基因调节是必不可少的。通过直接结合，macroH2A1.1抑制了基础聚ADP核糖聚合酶1（PARP-1）的活性，从而减少了核NAD ^+的消耗。NAD ^+的累积结果前体NMN可维持对呼吸至关重要的线粒体NAD ⁺库。我们的数据表明，包含macroH2A1.1的染色质通过限制核NAD ^+的消耗并在分化细胞中建立NAD ⁺前体的缓冲液来调节线粒体呼吸。