Nucleic Acids Research, Volume 50, Issue 14, 12 August 2022, Pages 7873–7888, https://doi.org/10.1093/nar/gkac585

DBC1 is a key positive regulator of enhancer epigenomic writers KMT2D and p300

Hwa Jin Kim, Sue Jin Moon, Sanghoon Hong, Hong-Hee Won, Jeong Hoon Kim

Abstract

Histone modification is a key epigenetic mechanism for regulation of chromatin dynamics and gene expression. Deleted in breast cancer 1 (DBC1) has been shown to act as a negative regulator of epigenetic modifiers and as a co-activator for nuclear receptors and other transcription factors. However, little is known about the role of DBC1 in the regulation of histone modifications and chromatin landscapes. Here, we analyzed genome-wide profiles of active enhancer and promoter marks in colorectal cancer cells and report DBC1 as a critical positive regulator of histone epigenetic writers KMT2D (H3K4 methyltransferase) and p300 (histone acetyltransferase). DBC1 is required for establishing the landscape of active enhancers, for genome-wide chromatin binding and enhancer recruitment of KMT2D and p300, and for gene activation involved in colorectal cancer progression. DBC1 interacts directly with KMT2D and p300, and enhances KMT2D-mediated histone H3K4 methylation (H3K4me1/2/3) and p300-mediated H3 acetylation. Importantly, DBC1 contributes to super-enhancer formation and function by facilitating the recruitment of KMT2D and p300 and by enhancing their functional interaction and cooperative cross-talk. Our results highlight the critical role of DBC1 as a key positive regulator of KMT2D and p300, and provide insights into regulatory mechanisms underlying the interplay between the enhancer epigenomic writers in enhancer activation.