Cell
Volume 165, Issue 2, 7 April 2016, Pages 331-342
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Article
Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

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Highlights

  • RACK7 binds a large set of active enhancers including almost all super-enhancers

  • RACK7 recruits KDM5C to enhancer regions and negatively regulates enhancer H3K4me3

  • Loss of RACK7 or KDM5C results in further activation of their target enhancers

  • RACK7 exerts tumor-suppressive function in part by repressing S100A oncogenes

Summary

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.

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