Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

Abstract

Summary 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.

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

“…In line with loss of TF binding and the associated ability to recruit co‐activators, H3K27ac was lost from the enhancer of Esrrb but not Nanog . Similarly to acetylation, H3K4me3, for which a correlation with enhancer activity is less well established (Pekowska et al , 2011; Outchkourov et al , 2013; Shen et al , 2016; Henriques et al , 2018), was also maintained in Esrrb‐GFP negative cells at the enhancer of Nanog but not Esrrb . Loss of H3K4me1 has been proposed to be a key step in enhancer decommissioning (preprint: Agarwal et al , 2017; Cao et al , 2018; Whyte et al , 2012; Yan et al , 2018), though a direct function for this mark remains controversial (Dorighi et al , 2017; Cao et al , 2018; Yan et al , 2018).…”

Histone Marks in the ‘Driver’s Seat’: Functional Roles in Steering the Transcription Cycle

“…This reduction of enhancer activity is thought to be important to prevent enhancers from becoming overactive, which is associated with an oncogenic state. The Shi laboratory found that the histone H3 K4 lysine demethylase 5C (KDM5C) is recruited to enhancers through receptor for activated C-kinase 7 (RACK7), and then converts H3K4me3 to H3K4me1 after hormone stimulation, in order to reduce enhancer activity [106]. They further demonstrated that knockout of RACK7 reduces KDM5C occupancy at enhancers and results in “overactive enhancers,” and also increases tumorigenicity of breast cancer cells [106].…”

“…The Shi laboratory found that the histone H3 K4 lysine demethylase 5C (KDM5C) is recruited to enhancers through receptor for activated C-kinase 7 (RACK7), and then converts H3K4me3 to H3K4me1 after hormone stimulation, in order to reduce enhancer activity [106]. They further demonstrated that knockout of RACK7 reduces KDM5C occupancy at enhancers and results in “overactive enhancers,” and also increases tumorigenicity of breast cancer cells [106]. Taken together, these studies suggest that the potential mechanistic roles of these marks in enhancer function, either in promoting eRNA transcription or communication with the promoter to impact mRNA transcription, still require further study.…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…Silencing JARID1B reduced H3K4me3 at promoters of self-renewal genes and spread H3K4 methylation to gene bodies and enhancer boundaries while promoting expression of lineage-specific genes [30]. Similarly, JARID1C can regulate the ratio of H3K4me1 to H3K4me3 at both enhancers and super-enhancers to modulate their levels of activity [31, 32]. …”