Histone H3 lysine 4 mono-methylation (H3K4me1) marks poised or active enhancers. KMT2C (MLL3) and KMT2D (MLL4) catalyze H3K4me1, but their histone methyltransferase activities are largely dispensable for transcription during early embryogenesis in mammals. To better understand the role of H3K4me1 in enhancer function, we analyze dynamic enhancer-promoter (E-P) interactions and gene expression during neural differentiation of the mouse embryonic stem cells. We found that KMT2C/D catalytic activities were only required for H3K4me1 and E-P contacts at a subset of candidate enhancers, induced upon neural differentiation. By contrast, a majority of enhancers retained H3K4me1 in KMT2C/D catalytic mutant cells. Surprisingly, H3K4me1 signals at these KMT2C/D-independent sites were reduced after acute depletion of KMT2B, resulting in aggravated transcriptional defects. Our observations therefore implicate KMT2B in the catalysis of H3K4me1 at enhancers and provide additional support for an active role of H3K4me1 in enhancer-promoter interactions and transcription in mammalian cells.

组蛋白 H3 赖氨酸 4 单甲基化 (H3K4me1) 标记稳定或活跃的增强子。 KMT2C (MLL3) 和 KMT2D (MLL4) 催化 H3K4me1，但它们的组蛋白甲基转移酶活性对于哺乳动物早期胚胎发生过程中的转录来说基本上是可有可无的。为了更好地了解 H3K4me1 在增强子功能中的作用，我们分析了小鼠胚胎干细胞神经分化过程中的动态增强子-启动子 (EP) 相互作用和基因表达。我们发现，KMT2C/D 催化活性仅是在神经分化时诱导的候选增强子子集上的 H3K4me1 和 EP 接触所必需的。相比之下，KMT2C/D 催化突变细胞中大多数增强子保留了 H3K4me1。令人惊讶的是，这些 KMT2C/D 独立位点的 H3K4me1 信号在 KMT2B 急性耗竭后减少，导致转录缺陷加剧。因此，我们的观察表明 KMT2B 参与了增强子处 H3K4me1 的催化，并为 H3K4me1 在哺乳动物细胞中增强子-启动子相互作用和转录中的积极作用提供了额外的支持。