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Abstract：
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.
摘要：
组蛋白H3赖氨酸4单甲基化(H3K4me1)标志着平衡的或有活性的增强子。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在很大程度上是不必要的。为了更好地理解H3K4me1在增强剂功能中的作用，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（E-P）相互作用和基因表达。我们发现KMT2C/D催化活性仅对于H3K4me1和E-P在候选增强剂的子集接触是必需的，诱导神经分化。相比之下,大多数增强子在KMT2C/D催化突变细胞中保留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，我们的观察结果暗示KMT2B在增强子上催化H3K4me1，并为H3K4me1在增强子-启动子相互作用和哺乳动物细胞转录中的积极作用提供了额外的支持。
