Song Mingzi, Fang Fei, Dai Xin, Yu Liming, Fang Mingming, Xu Yong
Department of Physiology, Jiangsu Jiankang Vocational College, Nanjing, Jiangsu, China.
Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Jiangsu, China.
FEBS Lett. 2017 Mar;591(6):934-945. doi: 10.1002/1873-3468.12601. Epub 2017 Mar 8.
Tumor necrosis factor alpha (TNF-α) is a prototypical proinflammatory cytokine that can elicit strong inflammation in macrophages by activating NF-κB. The underlying epigenetic mechanism is obscure. We show here that megakaryocytic leukemia 1 (MKL1) is an epigenetic mediator of TNF-α-induced proinflammatory transcription. Overexpression of a dominant negative form of MKL1 abrogates TNF-α-induced transactivation of proinflammatory genes. Proteomic analysis identifies the histone H3K4 trimethyltransferase ASH2 as a potential cofactor for MKL1. In response to TNF-α stimulation, ASH2 is recruited by MKL1 and interacts with MKL1 to catalyze H3K4 di- and trimethylation. ASH2 modulates proinflammatory transcription at least in part by altering the affinity of p65 for target promoters. Together, our data support an interplay between MKL1 and ASH2 to promote TNF-α-induced proinflammatory transcription in macrophages.
肿瘤坏死因子α（TNF-α）是一种典型的促炎细胞因子，可通过激活核因子κB（NF-κB）在巨噬细胞中引发强烈炎症。其潜在的表观遗传机制尚不清楚。我们在此表明巨核细胞白血病1（MKL1）是TNF-α诱导的促炎转录的表观遗传介质。MKL1显性负性形式的过表达消除了TNF-α诱导的促炎基因的反式激活。蛋白质组学分析确定组蛋白H3K4三甲基转移酶ASH2是MKL1的潜在辅因子。响应TNF-α刺激，ASH2被MKL1招募并与MKL1相互作用以催化H3K4二甲基化和三甲基化。ASH2至少部分地通过改变p65对靶启动子的亲和力来调节促炎转录。总之，我们的数据支持MKL1和ASH2之间的相互作用，以促进巨噬细胞中TNF-α诱导的促炎转录。
