Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes [gene expression]. Mus musculus

The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that the ESC master transcription factors and Mediator form “super-enhancers” at most genes known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4, Sox2, Nanog, Klf4, Esrrb and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in vivo and in reporter vectors. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. These results implicate super-enhancers in the control of mammalian cell identity and differentiation. Overall design: Time-course of gene expression following shRNA knockdown of Oct4 and Med12.