The distribution and composition of cis-regulatory modules composed of transcription factor (TF) binding site (TFBS) clusters in promoters substantially determine gene expression patterns and TF targets. TF knockdown experiments have revealed that TF binding profiles and gene expression levels are correlated.

Multiple information-dense TFBS clusters in promoters appear to protect promoters from effects of deleterious binding site mutations in a single TFBS that would otherwise alter regulation of these genes.

The distinctive organization and combination of TFBSs and regulatory modules in promoters dictates specific expression patterns within a set of genes1. Clustering of multiple adjacent binding sites for the same TF (homotypic clusters) and for different TFs (heterotypic clusters) defines cis-regulatory modules (CRMs) in human gene promoters. Experimental studies have shown that these clusters can reinforce (and in some instances, amplify) the impact of individual TFBSs on gene expression through increasing binding affinities, facilitated diffusion mechanisms and funnel effects2.