Department of Biochemistry and Molecular Biology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Sci Signal. 2013 Dec 10;6(305):ra107. doi: 10.1126/scisignal.2004633.
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. 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 Lys(27) of histone H3 (H3K27), which is associated with gene repression. IFN-γ and CIITA act to both promote the abundance of PRC2 subunits, which are not normally present during muscle differentation, and recruit the PRC2 complex to block myogenesis. 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.
炎症细胞因子干扰素-γ（IFN-γ）协调着多种基本生理过程。IFN-γ 和 II 类转录激活物（CIITA）在炎症反应中抑制肌肉发育方面发挥着重要作用。我们描述了 IFN-γ 和 CIITA 通过抑制炎症状态下的肌细胞基因表达来抑制肌生成的机制。在小鼠中，循环中 IFN-γ 含量的增加导致肌肉纤维中多梳抑制复合物 2（PRC2）的丰度增加，而 PRC2 在成年组织中通常不存在于肌肉中。我们表明，CIITA 首先与 Jumonji 家族蛋白 JARID2 相互作用，JARID2 是 PRC2 的非催化亚基，它导致在靶启动子处被磷酸化的 RNA 聚合酶 II（RNAPII）暂停。PRC2 复合物的其他亚基，包括催化亚基 EZH2，以 JARID2 依赖的方式被募集，这与 RNAPII 的丢失和组蛋白 H3（H3K27）赖氨酸 27 的甲基化同时发生，H3K27 的甲基化与基因沉默有关。IFN-γ 和 CIITA 既促进了 PRC2 亚基的丰度增加，这些亚基在肌肉分化过程中通常不存在，又募集了 PRC2 复合物来阻止肌生成。总之，这些数据表明，IFN-γ 的增加通过一个多步骤的机制重置了成肌细胞的命运，最终导致 PRC2 募集以沉默肌肉特异性基因。
