Josefowicz Steven Z, Shimada Miho, Armache Anja, Li Charles H, Miller Rand M, Lin Shu, Yang Aerin, Dill Brian D, Molina Henrik, Park Hee-Sung, Garcia Benjamin A, Taunton Jack, Roeder Robert G, Allis C David
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
Mol Cell. 2016 Oct 20;64(2):347-361. doi: 10.1016/j.molcel.2016.09.026.
The inflammatory response requires coordinated activation of both transcription factors and chromatin to induce transcription for defense against pathogens and environmental insults. We sought to elucidate the connections between inflammatory signaling pathways and chromatin through genomic footprinting of kinase activity and unbiased identification of prominent histone phosphorylation events. We identified H3 serine 28 phosphorylation (H3S28ph) as the principal stimulation-dependent histone modification and observed its enrichment at induced genes in mouse macrophages stimulated with bacterial lipopolysaccharide. Using pharmacological and genetic approaches, we identified mitogen- and stress-activated protein kinases (MSKs) as primary mediators of H3S28ph in macrophages. Cell-free transcription assays demonstrated that H3S28ph directly promotes p300/CBP-dependent transcription. Further, MSKs can activate both signal-responsive transcription factors and the chromatin template with additive effects on transcription. Specific inhibition of MSKs in macrophages selectively reduced transcription of stimulation-induced genes. Our results suggest that MSKs incorporate upstream signaling inputs and control multiple downstream regulators of inducible transcription.
炎症反应需要转录因子和染色质的协同激活，以诱导转录从而抵御病原体和环境损伤。我们试图通过激酶活性的基因组足迹分析和对显著组蛋白磷酸化事件的无偏鉴定，阐明炎症信号通路与染色质之间的联系。我们将组蛋白H3丝氨酸28磷酸化（H3S28ph）鉴定为主要的刺激依赖性组蛋白修饰，并观察到其在细菌脂多糖刺激的小鼠巨噬细胞中诱导基因处富集。使用药理学和遗传学方法，我们确定丝裂原和应激激活蛋白激酶（MSK）是巨噬细胞中H3S28ph的主要介导因子。无细胞转录分析表明，H3S28ph直接促进p300/CBP依赖性转录。此外，MSK可以激活信号响应转录因子和染色质模板，对转录具有累加效应。在巨噬细胞中特异性抑制MSK可选择性降低刺激诱导基因的转录。我们的结果表明，MSK整合上游信号输入并控制诱导转录的多个下游调节因子。
