A common assumption in studying gene transcription is that there are ‘master regulators’ that are required for gene regulation. Gurdeep Singh from Professor Jennifer Mitchell’s laboratory challenges this view in the latest Genome Research by showing that gene transcription can be precisely regulated by a diverse suite of factors, without any specific master regulators. This is a significant new insight into a major challenge of the post‐genomic era: determining the ‘cis‐regulatory code’ that relates DNA sequences to gene expression in a specific cell type.

Singh’s evolutionary analysis used machine learning to reveal conserved high enhancer feature (CHEF) regions containing a diverse array of transcription factor binding sites (TFBS). Active stem cell enhancers are found to contain over 10 TFBS out of a repertoire of 70 different TFBS.

Previous studies concatenated multiple master regulatory sequences, but were unable to reach the output level of natural enhancers. Synthetic CHEF enhancers with multiple TFBS drove expression in mouse embryonic stem cells with at a level much greater than synthetic enhancers containing repeated ‘master’ regulator TFBS (Sox2/Oct4). This is the first demonstration of the necessary and sufficient determinants of a cis‐regulatory code.

The artwork from Ian Hsu of the Moses lab commissioned for this study shows a diverse group of people, representing diverse transcription factors dancing on enhancer DNA. You can read more about this research in ”A flexible repertoire of transcription factor binding sites and a diversity threshold determines enhancer activity in embryonic stem cells”.