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Cell. 2016 Apr 7;165(2):331-42. doi: 10.1016/j.cell.2016.02.064.

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex.

Author information

1
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.
2
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.
3
Newborn Medicine Division, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
4
Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
5
Department of System Biology, Institutes of Biomedical Sciences, Fudan University, 138 Yixue Yuan Road, Shanghai 200032, China.
6
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; Division of Endocrinology, Brigham and Women Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
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. Electronic address: yshi@hms.harvard.edu.
8
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; Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China. Electronic address: fei_lan@fudan.edu.cn.

Abstract

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.

PMID:
27058665
PMCID:
PMC4826479
DOI:
10.1016/j.cell.2016.02.064
[Indexed for MEDLINE]
Free PMC Article

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