H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation.

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. [Display omitted] • H3K4me1 promotes enhancer-promoter contacts in neural progenitor cell differentiation • H3K4me1 can occur at candidate enhancers due to KMT2C/D-independent mechanisms • KMT2B contributes to H3K4me1 at KMT2C/D-independent candidate enhancers • KMT2B loss aggravates the transcriptional defects in KMT2C/D-catalytic-deficient cells Despite the association of H3K4me1 with distal enhancers, inactivation of KMT2C/D, the major mono-methyltransferases for H3K4me1, results in mild transcriptional defects in cells. Kubo et al. show that KMT2B contributes to KMT2C/D-independent H3K4me1 at enhancers and transcription. Their results suggest that H3K4me1 indeed facilitates enhancer-promoter contacts and enhancer-driven transcription during differentiation. [ABSTRACT FROM AUTHOR]