A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (RNA-Seq II)

Primed enhancers are marked by histone H3K4 mono-methylation (H3K4me1), and the conversion to active enhancers involves acetylation of histone H3K27 (H3K27Ac). However, whether active enhancers are regulated remains unclear. Here we report a biochemical complex consisting of a potential chromatin reader (RACK7) and a histone demethylase (KDM5C) that occupies many active enhancers in a breast cancer cell line. Loss of RACK7 or KDM5C results in hyperactive enhancers marked by H3K4me3 and H3K27Ac, and characterized by an increased eRNA transcription and elevated expression of nearby genes. Loss of RACK7 or KDM5C also leads to increased cell invasion and migration, and enhanced tumor growth. We propose that RACK7/KDM5C functions as an enhancer “brake” to ensure appropriate enhancer activities in the cell. Our findings provide important insight into histone H3K4 methylation dynamics at enhancers and reveal a molecular mechanism that controls the activities of active enhancers, which when compromised, can contribute to tumorigenesis. Overall design: nascent RNA-seq of parental and RACK7-KO cells

4

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