Induction of nuclear factor of activated T cell cytoplasmic 1 (NFATc1) by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) is essential for macrophage differentiation into osteoclasts (OCs), but the underlying mechanisms remain unclear. The ability of poly(ADP-ribose) polymerase 1 (PARP1) to poly-ADP-ribosylate NFATc1 in T cells prompted us to investigate the PARP1 and NFATc1 interaction during osteoclastogenesis. However, extensive studies failed to directly link PARP1 to NFATc1. A combination of transcriptomics and proteomics studies was then used to identify PARP1 targets under these conditions. These unbiased approaches in conjunction with site-directed mutagenesis studies revealed that PARP1 inhibited NFATc1 expression and OC formation by ADP-ribosylating histone H2B at serine 7 and decreasing the occupancy of this histone variant at the NFATc1 promoter. The anti-osteoclastogenic function of PARP1 was confirmed in vivo in several mouse models of PARP1 loss-of-function or gain-of-function, including a novel model in which PARP1 was conditionally ablated in myeloid cells. Thus, PARP1 ADP-ribosylates H2B to negatively regulate NFATc1 expression and OC differentiation. © 2019 American Society for Bone and Mineral Research.

中文翻译：

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PARP1 阻碍 NFATc1 启动子处的组蛋白 H2B 占据以抑制破骨细胞分化。

巨噬细胞集落刺激因子 (M-CSF) 和 NF-κB 配体受体激活剂 (RANKL) 对活化 T 细胞胞质 1 (NFATc1) 的核因子的诱导对于巨噬细胞分化为破骨细胞 (OCs) 至关重要。仍不清楚。聚（ADP-核糖）聚合酶 1（PARP1）在 T 细胞中聚-ADP-核糖基化 NFATc1 的能力促使我们研究破骨细胞生成过程中 PARP1 和 NFATc1 的相互作用。然而，广泛的研究未能直接将 PARP1 与 NFATc1 联系起来。然后使用转录组学和蛋白质组学研究的组合来鉴定这些条件下的 PARP1 靶标。这些不偏不倚的方法与定点诱变研究相结合表明，PARP1 通过 ADP 核糖基化组蛋白 H2B 在丝氨酸 7 处抑制 NFATc1 表达和 OC 形成，并降低该组蛋白变体在 NFATc1 启动子处的占有率。PARP1 的抗破骨细胞功能在几种 PARP1 功能丧失或功能获得的小鼠模型中在体内得到证实，包括一种新模型，其中 PARP1 在骨髓细胞中被有条件地消融。因此，PARP1 ADP-核糖基化 H2B 以负调节 NFATc1 表达和 OC 分化。© 2019 美国骨与矿物研究学会。包括一种新模型，其中 PARP1 在骨髓细胞中被有条件地消融。因此，PARP1 ADP-核糖基化 H2B 以负调节 NFATc1 表达和 OC 分化。© 2019 美国骨与矿物研究学会。包括一种新模型，其中 PARP1 在骨髓细胞中被有条件地消融。因此，PARP1 ADP-核糖基化 H2B 以负调节 NFATc1 表达和 OC 分化。© 2019 美国骨与矿物研究学会。