Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, South Korea.
Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea.
Nucleic Acids Res. 2022 Aug 12;50(14):7873-7888. doi: 10.1093/nar/gkac585.
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.
组蛋白修饰是调节染色质动态和基因表达的关键表观遗传机制。乳腺癌缺失基因 1（DBC1）已被证明作为表观遗传修饰物的负调节剂以及核受体和其他转录因子的共激活剂发挥作用。然而，关于 DBC1 在组蛋白修饰和染色质景观调节中的作用知之甚少。在这里，我们分析了结直肠癌细胞中活性增强子和启动子标记的全基因组图谱，并报告 DBC1 是组蛋白表观遗传作家 KMT2D（H3K4 甲基转移酶）和 p300（组蛋白乙酰转移酶）的关键正调控因子。DBC1 对于建立活性增强子景观、KMT2D 和 p300 的全基因组染色质结合和增强子募集以及涉及结直肠癌细胞进展的基因激活是必需的。DBC1 与 KMT2D 和 p300 直接相互作用，并增强 KMT2D 介导的组蛋白 H3K4 甲基化（H3K4me1/2/3）和 p300 介导的 H3 乙酰化。重要的是，DBC1 通过促进 KMT2D 和 p300 的募集以及增强它们的功能相互作用和协同交叉对话，有助于超级增强子的形成和功能。我们的研究结果强调了 DBC1 作为 KMT2D 和 p300 的关键正调控因子的关键作用，并为增强子激活中增强子表观遗传作家之间相互作用的调控机制提供了新的见解。
