Ottawa Hospital Research Institute, University of Ottawa, Faculty of Medicine, Ottawa, ON K1K 8L6
Gene expression output is regulated by an intricate array of genetic and epigenetic factors. cis-regulatory DNA elements (CRMs), composed of clusters of transcription factor binding sites (TFBS) play crucial role in binding specificity and affinity of transcription factors to DNA and subsequent modulation of target gene expression output. Using genome-wide binding site analysis of key master transcription factors in muscle stem cells and mouse embryonic stem cells coupled with gene expression analysis we show that sequence variation within transcription factor binding motif determine the affinity landscape and epigenetic state of enhancers and their target gene expression. We show that variant sequences within TF binding motif have the same evolutionary constrains as the invariant sites. Finally, our data suggests that variation in TF binding motif constitute the genetic blueprint of the enhancer code and is crucial to establish a dynamic range of target gene expression output.