Taking inspiration from The Dance by Henri Matisse a diverse group of people, representing diverse transcription factor proteins, dance on enhancer DNA (red). This dynamic interaction of ten different transcription factors with the DNA is required for robust transcription output, represented by the fire and the emerging transcripts (white). Receding in the distance the DNA is occupied by nucleosomes (brown). Enhancers are an important part of the non-coding genome, critical for development, phenotype evolution and often mutated in disease contexts. Despite this importance, we lack a sequence level understanding of enhancers; the sequence code conferring enhancer activity was unknown even for well-studied cell types. In this issue, a conserved regulatory code of more than 70 transcription factor binding sequences was identified that drives gene expression in pluripotent stem cells. Using a diverse set of more than ten transcription factor binding sequences from this repertoire of 70 was sufficient to construct short synthetic enhancers with the activity of native enhancers. Transcription factor number and diversity are both important for enhancer activity revealing new insight into the regulatory code for pluripotent cells. This paper can be accessed on the latest edition of Genome Research.

Credit: Concept and Illustration by Ian Hsu.