ENAapplication/xmlftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959039/SRR959039.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959032/SRR959032.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959035/SRR959035.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959034/SRR959034.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959033/SRR959033.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959038/SRR959038.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959041/SRR959041.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959040/SRR959040.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959036/SRR959036.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR959/SRR959037/SRR959037.fastq.gzprimaryOK2000000GenomicsNIDDK, NIHhttps://www.ebi.ac.uk/ena/browser/view/PRJNA217448Mus 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 analyses of adipogenic TF (C/EBPalpha, C/EBPbeta, and PPARgamma) and Pol II profiles at D0 (day 0) and D2 (day 2) of adipogenesis in WT (MLL3-/-) and MLL4 KO (MLL3-/-;MLL4-/-) brown preadipocytes.ENAwide, wide/broad, broad, Genomes, Maps.mouse, mouse <Mus musculus>, house mouse.0.00.00.00.00.00falseMus musculusGenome-wide maps of adipogenic TFs during brown preadipocyte differentiation2022-05-122013-12-19PRJNA217448GSE504162436873410090