MKL1 定义了 NF-κB 依赖的炎症反应的 H3K4Me3 景观。

MKL1 defines the H3K4Me3 landscape for NF-κB dependent inflammatory response.

机构信息

Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.

State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China.

出版信息

Sci Rep. 2017 Mar 15;7(1):191. doi: 10.1038/s41598-017-00301-w.

Macrophage-dependent inflammatory response is considered a pivotal biological process that contributes to a host of diseases when aberrantly activated. The underlying epigenetic mechanism is not completely understood. We report here that MKL1 was both sufficient and necessary for p65-dependent pro-inflammatory transcriptional program in immortalized macrophages, in primary human and mouse macrophages, and in an animal model of systemic inflammation (endotoxic shock). Extensive chromatin immunoprecipitation (ChIP) profiling and ChIP-seq analyses revealed that MKL1 deficiency erased key histone modifications synonymous with transactivation on p65 target promoters. Specifically, MKL1 defined histone H3K4 trimethylation landscape for NF-κB dependent transcription. MKL1 recruited an H3K4 trimethyltransferase SET1 to the promoter regions of p65 target genes. There, our work has identified a novel modifier of p65-dependent pro-inflammatory transcription, which may serve as potential therapeutic targets in treating inflammation related diseases.

巨噬细胞依赖性炎症反应被认为是一种关键的生物学过程，当异常激活时会导致多种疾病。其潜在的表观遗传机制尚不完全清楚。我们在这里报告，MKL1 在永生化巨噬细胞、原代人和小鼠巨噬细胞以及全身性炎症（内毒素休克）的动物模型中，对于 p65 依赖性促炎转录程序既充分又必要。广泛的染色质免疫沉淀（ChIP）分析和 ChIP-seq 分析表明，MKL1 缺乏消除了与 p65 靶启动子上反式激活同义的关键组蛋白修饰。具体来说，MKL1 定义了 NF-κB 依赖转录的组蛋白 H3K4 三甲基化图谱。MKL1 将 H3K4 三甲基转移酶 SET1 募集到 p65 靶基因的启动子区域。在那里，我们的工作已经确定了 p65 依赖性促炎转录的一种新的调节剂，它可能成为治疗炎症相关疾病的潜在治疗靶点。