Abstract: Enhancer sequences increase gene transcription with the help of a co-activator complex, the Mediator. Another protein complex — cohesin — seems to work with Mediator to bring together enhancers and promoters. See Article p. 430 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.