Motif grammar: The basis of the language of gene expression

Collaboration of transcription factors (TFs) and their recognition motifs in DNA is the result of coevolution and forms the basis of gene regulation. However, the way how these short genomic sequences contribute to setting the level of gene products is not understood in sufficient detail. The biological problem to be solved by the cell is complex, because each gene requires a unique regulatory network in each cellular condition using the same genome. Thus far, only some components of these networks have been uncovered. In this review, we compiled the features and principles of the motif grammar, which dictates the characteristics and thus the likelihood of the interactions of the binding TFs and their coregulators. We present how sequence features provide specificity using, as examples, two major TF superfamilies, the bZIP proteins and nuclear receptors. We also discuss the phenomenon of “weak” (low affinity) binding sites, which appear to be components of several important genomic regulatory regions, but paradoxically are barely detectable by the currently used approaches. Assembling the complete set of regulatory regions composed of both weak and strong binding sites will allow one to get more comprehensive lists of factors playing roles in gene regulation, thus making possible the deeper understanding of regulatory networks.