来源：SIBCS
增强子是一类控制基因表达的重要调控元件，其借助于一组独特的染色质修饰以待发（primed）、准备（poised）和活化（active）三种状态存在。例如，H3K4me1与增强子的三种状态均有关联，这主要由MLL3/4所介导。单独的H3K4me1标记待发增强子。当与H3K27me3或H3K27Ac在一起时，这一组合的组蛋白修饰则进一步分别定义准备(H3K4me1/H3K27me3)和活化(H3K4me1/H3K27Ac)状态的增强子。将待发增强子转变为活化增强子是包括胚胎干细胞（ESC）分化在内的许多生物学过程中至关重要的一个步骤。
新出现的证据表明，增强子调节异常有可能导致了包括癌症在内的一些有害的影响。例如，一些参与改变增强子染色质景观的酶，如组蛋白甲基转移酶MLL2、MLL3和MLL4；H3K4me2/3特异性去甲基化酶KDM5C；乙酰转移酶CBP/p300；以及组蛋白H3变体H3.3，被发现在各种癌症中频繁突变。与之相一致，近期一些癌症基因组测序工作也鉴别出了一些调控癌基因和抑癌基因表达的增强子和超级增强子发生遗传突变。这些功能和基因组研究凸显了增强子和它们的调控具有的重要影响，当其受损时可以导致肿瘤发生。
本研究鉴别出了包含两个假定肿瘤抑制因子RACK7和KDM5C的一个染色质复合物。RACK7是一个潜在的染色质阅读器，KDM5C是一种组蛋白去甲基化酶。两者共同占据在包括几乎所有超级增强子在内的大量活化增强子上，发挥增强子负调控因子作用。本研究证实RACK7与KDM5C发生了互作，丧失RACK7可显著损害KDM5C定位到活化增强子上，表明RACK7对于KDM5C招募至增强子处起重要作用。
遗传删除乳腺癌细胞系ZR-75-30中的RACK7或KDM5C，可导致靶增强子过度激活，其以RACK7结合增强子H3K4me3增多，H3K4me1减少，eRNA水平增高为特征。这些无RACK7的ZR-75-30细胞还显示体外非依赖性生长、迁移和侵袭能力增强，以及小鼠移植瘤模型中肿瘤生长增强。同样地，KDM5C丧失也可以导致类似的细胞迁移和侵袭增强，进一步支持了这一观点：RACK7和KDM5C协同作用调控了与肿瘤发生相关的细胞过程。
这些研究结果揭示出活化增强子受到负调控，RACK7和KDM5C协同作用通过控制活化增强子处H3K4me1与H3K4me3的动态，充当了活化增强子的“刹车”。丧失这样的增强子监管机制可以导致细胞行为改变，有可能促成了肿瘤发生。
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原文信息
Cell. 2016 Apr 7;165(2):331-42.
Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex.
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.
•Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Key Laboratory of Epigenetics, Department of Cellular and Genetic Medicine, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
•Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China.
•Newborn Medicine Division, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
•Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
•Department of System Biology, Institutes of Biomedical Sciences, Fudan University, 138 Yixue Yuan Road, Shanghai 200032, China.
•Division of Endocrinology, Brigham and Women Hospital, Harvard Medical School, Boston, MA 02115, USA.
Regulation of enhancer activity is important for controlling gene expression programs. Here, we report that a biochemical complex containing 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.
Grant Support: R01 CA118487/CA/NCI NIH HHS/United States
PMID: 27058665
PMCID: PMC4826479
DOI: 10.1016/j.cell.2016.02.064
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