Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex.
Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex.
复制标题
RACK7-组蛋白去甲基酶复合物抑制增强子过度激活。
DOI：
10.1016/j.cell.2016.02.064
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发表时间：
2016-04-07
期刊：
影响因子：
64.5
通讯作者：
Lan F
中科院分区：
文献类型：
--
作者：
Shen H;Xu W;Guo R;Rong B;Gu L;Wang Z;He C;Zheng L;Hu X;Hu Z;Shao ZM;Yang P;Wu F;Shi YG;Shi Y;Lan F
增强子活性的调节对于控制基因表达程序是重要的。在这里，我们报告说，一个生化复合物，包含一个潜在的染色质阅读器，RACK 7和组蛋白赖氨酸4三甲基（H3 K4 me 3）特异性去甲基化酶KDM 5C占据许多活性增强子，包括几乎所有的超级增强子。RACK 7或KDM 5C的缺失导致增强子的过度激活，其特征在于H3 K4 me 3和H3 K27 Ac的沉积，以及eRNA和附近基因的转录增加。此外，RACK 7或KDM 5C的缺失导致S100 A癌基因和各种癌症相关表型的去抑制。我们的研究结果揭示了RACK 7/KDM 5C调节，组蛋白H3 K4 me 1和H3 K4 me 3之间的动态交换在活性增强子，代表了增强子活性的调节的额外层。我们提出RACK 7/KDM 5C作为增强子“刹车”发挥作用，以确保适当的增强子活性，当受到损害时，可能有助于肿瘤发生。
Regulation of enhancer activity is important for controlling gene expression programs. Here we report that a biochemical complex that contains a potential chromatin reader, RACK7 and the histone lysine 4 tri-methyl (H3K4me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes. Our findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4me3 at active enhancers, representing an additional layer of regulation of enhancer activity. We propose that RACK7/KDM5C functions as an enhancer “brake” to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis.