Interferon-γ resets muscle cell fate by stimulating the sequential recruitment of JARID2 and PRC2 to promoters to repress myogenesis.
Interferon-γ resets muscle cell fate by stimulating the sequential recruitment of JARID2 and PRC2 to promoters to repress myogenesis.
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DOI：
10.1126/scisignal.2004633
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发表时间：
2013-12-10
影响因子：
7.3
通讯作者：
Davie JK
中科院分区：
文献类型：
--
作者：
Londhe P;Davie JK
炎症细胞因子干扰素-γ (IFN-γ) 协调多种基本生理过程。 IFN-γ 和 II 类反式激活因子 (CIITA) 在炎症反应期间抑制肌肉发育中发挥重要作用。在这里，我们描述了 IFN-γ 和 CIITA 通过抑制炎症肌肉细胞中的基因表达来抑制肌生成的机制。在小鼠中，循环中 IFN-γ 量的增加导致肌纤维中多梳抑制复合物 2 (PRC2) 的丰度增加，而在成人中，PRC2 在这种组织中通常不存在。我们发现 CIITA 首先与 Jumonji 家族蛋白 JARID2（PRC2 的非催化亚基）相互作用，导致丝氨酸 5 磷酸化的 RNA 聚合酶 II (RNAPII) 在目标启动子处暂停。然后，PRC2 复合体的其他亚基（包括催化亚基 EZH2）以 JARID2 依赖性方式招募，同时发生 RNAPII 丢失和组蛋白 H3 (H3K27) 赖氨酸 27 甲基化（与基因抑制相关）。 CIITA 和 IFN-γ 通过诱导 PRC2 复合物（通常不存在于分化的肌肉细胞中）的形成和募集来阻断培养物中的肌生成。总之，这些数据表明，增加的 IFN-γ 量通过多步骤机制重置肌原细胞命运，最终招募 PRC2 来沉默肌肉特异性基因。
The inflammatory cytokine interferon-γ (IFN-γ) orchestrates a diverse array of fundamental physiological processes. IFN-γ and the class II transactivator (CIITA) play essential roles in inhibiting muscle development during the inflammatory response. Here, we describe the mechanism through which IFN-γ and CIITA inhibit myogenesis by repressing gene expression in muscle cells subjected to inflammation. In mice, the presence of increased amounts of circulating IFN-γ resulted in the increased abundance of polycomb repressive complex 2 (PRC2) in muscle fibers, a tissue in which PRC2 is not normally present in the adult. We showed that CIITA first interacted with the Jumonji family protein JARID2, a noncatalytic subunit of PRC2, which caused an RNA polymerase II (RNAPII), phosphorylated at serine 5, to pause at target promoters. Additional subunits of the PRC2 complex, including the catalytic subunit EZH2, were then recruited in a JARID2-dependent manner that was concurrent with the loss of RNAPII and the methylation of lysine 27 of histone H3 (H3K27), which is associated with gene repression. By inducing the formation and recruitment of the PRC2 complex, which is normally not present in differentiated muscle cells, CIITA and IFN-γ block myogenesis in culture. Together, these data indicate that increased amounts of IFN-γ reset myogenic cell fate through a multistep mechanism that culminates in the recruitment of PRC2 to silence muscle-specific genes.
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