ENAapplication/xmlftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959917/SRR959917.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959907/SRR959907.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959900/SRR959900.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959920/SRR959920.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959914/SRR959914.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959904/SRR959904.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959913/SRR959913.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959918/SRR959918.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959908/SRR959908.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959921/SRR959921.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959911/SRR959911.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959901/SRR959901.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959906/SRR959906.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959903/SRR959903.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959916/SRR959916.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959922/SRR959922.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959912/SRR959912.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959909/SRR959909.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959905/SRR959905.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959919/SRR959919.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959923/SRR959923.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959915/SRR959915.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959910/SRR959910.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959902/SRR959902.fastq.gzprimaryOK2000000GenomicsNIDDK, NIHhttps://www.ebi.ac.uk/ena/browser/view/PRJNA217529Mus musculusEnhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for the deposition of H3K4me1/2 on enhancers remain elusive. Furthermore, the functions of these methyltransferases on enhancers and associated cell-type-specific gene expression are poorly understood. Here, we identify MLL4 (KMT2D) as a major H3K4 mono- and di-methyltransferase in mammalian cells. Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of MLL4 dramatically decreases H3K4me1/2 and H3K27ac on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Finally, we provide evidence that lineage-determining TFs recruit and require MLL4 to establish enhancers critical for cell-type-specific gene expression. Together, these results identify MLL4 as an H3K4 mono-/di-methyltransferase required for enhancer activation during cell differentiation. Overall design: ChIP-Seq of MyoD, MLL4 and histone modifications (H3K4me1, H3K4me3, and H3K27ac) in adenoviral GFP- or Cre-infected MLL3-/-;MLL4-flox/flox cells. Preadipocytes: brown preadipocytes before differentiation. D5 myocytes: 5 days after MyoD-induced myogenesis of brown preadipocytes.ENAKABUK1, NAU, Nau, Oca3, bHLHc1, HRX2, Myod-1, ALR, KMT2B, wide/broad, CAGL114, Genomes, Tyrp, brown., Mdrf, Maps, Dmyd, BC058659, broad, CG10250, WBP7, MLL1B, BC032281, MLL2, Mll2, TNRC21, b, MLL4, C430014K11Rik, Mll4, wide, MyoD, MYOD, WBP-7, PUM, DmelCG10250, KMS, TRP-1, AAD10, isa, TRP1, myogenesis, AI503393, MYF3, TRX2mouse, mouse <Mus musculus>, house mouse.0.00.00.00.00.00falseMus musculusGenome-wide maps of MyoD, MLL4 and histone modifications during MyoD-induced myogenesis in WT and MLL4-/- brown preadipocytes2022-05-122013-12-19PRJNA217529GSE504652436873410090