Mediator and cohesin connect gene expression and chromatin architecture

Transcription factors control cell-specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. Here we report that mediator and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect two DNA segments. The cohesin-loading factor Nipbl is associated with mediator–cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell-type-specific DNA loops linked to the gene expression program of each cell. Mediator and cohesin in control of stem-cell state The control of embryonic stem-cell state is not yet fully understood, but is fundamental to our knowledge of human development and to making progress in regenerative medicine. The gene-expression programs that make stem cells pluripotent are controlled by transcription factors — such as Oct4, Sox2 and Nanog — in a process thought to involve gene activation through DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter. Two factors, Mediator and cohesin, are shown here to connect the enhancers and core promoters of active genes in embryonic stem cells by generating cell-type-specific DNA loops linked to the gene-expression program of each cell. These results suggest that diseases caused by mutations in Mediator and cohesin — including Opitz–Kaveggia syndrome, Lujan syndrome, schizophrenia and Cornelia de Lange syndrome — are associated with defects in the cell-type-specific chromatin structure that is established by these protein complexes. Gene activation may involve the formation of a DNA loop that connects enhancer-bound transcription factors with the transcription apparatus at the core promoter. But this process is not well understood. Here, two proteins, mediator and cohesin, are shown to connect the enhancers and core promoters of active genes in embryonic stem cells. These proteins seem to generate cell-type-specific DNA loops linked to the gene expres