Spurious transcription factor binding: non-functional or genetically redundant?
Bottom Line: Transcription factor binding sites (TFBSs) on the DNA are generally accepted as the key nodes of gene control.However, the multitudes of TFBSs identified in genome-wide studies, some of them seemingly unconstrained in evolution, have prompted the view that in many cases TF binding may serve no biological function.This has significant implications for interpreting the phenotypic effects of TFBS mutations, particularly in the context of genome-wide association studies for complex traits.
Affiliation: Babraham Institute, Cambridge, UK.Show MeSH
Related in: MedlinePlus
Mentions: A second, potentially counterintuitive consequence of genetic redundancy is that groups of TFBSs may be in epistatic relationships with each other that are not observable under normal conditions. While classically described for redundant protein-coding genes 101,102, this phenomenon likely also applies to regulatory sequences. In particular, variation at a TFBS that seems unconstrained (or ‘spurious’) in healthy individuals may turn out to determine whether mutations at other, perhaps ‘stronger’ TFBSs will lead to disease onset (Fig. 3A). One real-life example of this can be seen in the regulatory logic of the homeobox gene cog-1 in Caenorhabditis elegans. This gene is controlled by a zinc-finger TF (CHE1) that is recruited to two TFBSs in the cog-1 upstream region. It has been shown that the deletion of the weaker ‘distal’ TFBS does not affect the levels of cog-1 expression, at least in an in vitro reporter assay. However, when the stronger ‘proximal’ CHE1 TFBS is deleted, the ‘distal’ TFBS is able to maintain 50% of the normal cog-1 levels. The deletion of both ‘proximal’ and ‘distal’ TFBSs abolishes cog-1 expression altogether 103.