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Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex #MMPMID27058665
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
Cell 2016[Apr]; 165 (2): 331-42 PMID27058665show ga
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.