Spurious transcription factor binding: Non‐functional or genetically redundant?

Abstract

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. Yet, insights from transcriptional biochemistry, population genetics and functional genomics suggest that rather than segregating into ‘functional’ or ‘non-functional’, TFBS inputs to their target genes may be generally cumulative, with varying degrees of potency and redundancy. As TFBS redundancy can be diminished by mutations and environmental stress, some of the apparently ‘spurious’ sites may turn out to be important for maintaining adequate transcriptional regulation under these conditions. This has significant implications for interpreting the phenotypic effects of TFBS mutations, particularly in the context of genome-wide association studies for complex traits.

Ehrlichia chaffeensis TRP32 Is a Nucleomodulin That Directly Regulates Expression of Host Genes Governing Differentiation and Proliferation

“…When expression of TRP32 targets was examined, we found that 80% were differentially regulated during infection. This is an expected result, as transcription factors typically bind many nonfunctional sites, with reports of as many as ϳ50 to 99.9% of transcription factor-bound sites not having a clear functional role (42,43). Most gene targets showed differences in expression primarily at 72 hpi, although some showed changes at 48 hpi as well.…”

Population Variation and Genetic Control of Modular Chromatin Architecture in Humans

“…Alternatively, these sequences may be subject to spurious regulatory activity, which would explain the findings that: (1) only a minority of genetically variable TF-DNA binding events result in differential gene expression (this work), (2) a large portion of TF-DNA binding events have no functional consequence (Cusanovich et al, 2014;Farnham, 2009), and (3) TF binding sites tend to experience rapid turnover (Dermitzakis and Clark, 2002;Villar et al, 2015). Another complementary interpretation involves the model of dose-dependent gene activation in which several TF binding sites in multiple elements cumulatively contribute to gene expression (Spivakov, 2014). Under this model, loss of TF-DNA binding at one binding site would have little to no discernible functional consequence as long as the other implicated TF binding sites remain intact.…”

Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection

“…Yet, the very same genes are dependent on T-bet in immature NK cells, at a stage where Zeb2 is expressed at low and ineffective levels. This suggests that both TFs contribute to transcriptional activation in a cumulative rather than synergistic fashion, a notion arising from the analysis of genome-wide studies (Spivakov, 2014). Other TFs may also cooperate with T-bet and Zeb2 to confer robustness to the regulatory network as Zeb2 is known to recruit several transcriptional cofactors (Conidi et al, 2011).…”