RESUMEN

Enhancers 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 H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). 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 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation. DOI: http://dx.doi.org/10.7554/eLife.01503.001.

Asunto(s)

Adipocitos/enzimología , Adipogénesis , Proteínas de Unión al ADN/metabolismo , Elementos de Facilitación Genéticos , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Células Musculares/enzimología , Desarrollo de Músculos , Células 3T3-L1 , Animales , Sitios de Unión , Linaje de la Célula , Biología Computacional , ADN Polimerasa II/metabolismo , Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica , Genómica/métodos , N-Metiltransferasa de Histona-Lisina/deficiencia , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Complejo Mediador/metabolismo , Metilación , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas , Factores de Tiempo , Factores de Transcripción/metabolismo , Transfección