Eukaryotic gene expression is orchestrated by a complex interplay between cis-regulatory elements (CREs) and the proteins that bind to and interact with those DNA sites, including transcription factors (TFs) and various types of chromatin proteins. In metazoan species the cis-elements that regulate gene expression can be found within the gene, directly upstream near the transcription start site, or long distances away from the regulated gene sequence.  These long-distance CREs interact with each other and with gene promoters through chromatin loops, dynamic structures that are unique to specific cell types and cell states.

Many TFs act by recruiting specific chromatin proteins or chromatin remodeling complexes to the CREs, thereby altering their activity and accessibility.  In mammals, one class of chromatin-modifying TFs, called KRAB-ZNFs, dominate the genomic landscape. The KRAB-ZNF family of genes is relatively ancient, but has expanded to a large family, through series of tandem segmental duplications, only in mammals.