Genome-wide transcription factor binding: beyond direct target regulation

Abstract

The binding of transcription factors to specific DNA target sequences is the fundamental basis of gene regulatory networks. Chromatin immunoprecipitation combined with DNA tiling arrays or high-throughput sequencing (ChIP-chip and ChIP-seq, respectively) has been used in many recent studies that detail the binding sites of various transcription factors. Surprisingly, data from a variety of model organisms and tissues have demonstrated that transcription factors vary greatly in their number of genomic binding sites, and that binding events can significantly exceed the number of known or possible direct gene targets. Thus, current understanding of transcription factor function must expand to encompass what role, if any, binding might have outside of direct transcriptional target regulation. In this review, we discuss the biological significance of genome-wide binding of transcription factors and present models that can account for this phenomenon.

Figure 1. Examples of regulatory motifs used to control transcription

A variety of mechanisms, or regulatory motifs, are used to control the expression of specific gene targets over unique spacial (eg. specific tissue types) and/or temporal contexts. (A) Feed-forward regulation permits temporal control of the targets of a single transcription factor. A transcription factor, represented by the grey circle, binds to multiple DNA targets (blue and black targets), but only activates one of them (Time 1). The gene target that it activates (red circle) can then also bind to one of the same gene targets as the original factor (black), and together they activate transcription (Time 2). (B) The use of cooperative factors permits transcription factors to be expressed widely, but discriminately activate gene targets. A single transcription factor, again represented by the grey circle, binds to multiple gene targets, activating one (the blue line) consistently, regardless of the cellular context (either tissue type or time). Other targets that it binds to in both cases (black and red targets), are activated only if they are also bound by another factor (compare activation of black and red targets between location/time 1 and 2), expressed specifically in that cellular condition.

Figure 2. Genome-wide binding and the evolution of transcriptional networks

The ability of certain transcription factors to bind widely throughout the genome could permit the evolution of new transcriptional regulatory networks in a relatively limited number of events. This could mean that genome-wide binding might actually serve an evolutionary advantage in cells, permitting them to more easily acquire new networks and phenotypes, as a result of the different genes involved in those networks. (A) Schematic representation of a transcription factor that binds to many sites throughout the genome and regulates transcription at a subset of these sites in a single input motif, in which it alone regulates the expression of the targets at which it binds. (A') Duplication and sequence divergence of this factor can give rise to a family member with similar DNA binding characteristics but transcriptional regulation of an overlapping yet distinct set of genes. The more promiscuous the binding of factor A and A', the greater the subset of genes they have the potential to influence and the greater potential for target diversity between A and A'. Therefore, changing from A to A' could lead to the generation of a new complex program by a single factor modification. (B and B') If the cellular phenotype conferred by the set of genes regulated in A and A' have some selective advantage, then the single input motif can be refined by the gradual super-imposition of a feed-forward motif to achieve temporal regulation and more robust kinetics. (C) It is also possible for feed-forward motifs to degenerate into simple cascades of regulated genes over time if subsequent mutations in the original factor limit the set of genes that can be directly bound, further separating the two networks that originally came from a common progenitor.