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Spurious transcription factor binding: non-functional or genetically redundant?

Spivakov M - Bioessays (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Babraham Institute, Cambridge, UK.

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Related in: MedlinePlus

The ‘dose of activation’ view of TFBS action and the emergence of redundancy. A: The probabilistic model of transcriptional initiation involving transient ‘hit-and-run’ interactions (Fig. 1) suggests that TF-binding events at multiple TFBSs provide generally cumulative inputs (‘doses of activation’) to their target promoters. B: When the total input from a group of TFBSs narrowly reaches the minimum tolerable ‘dose’, mutations at individual TFBSs will be poorly tolerated. C: If, on the other hand, the total inputs exceed this dose, the system becomes partially redundant and mutations at individual TFBSs may not cause significant changes in gene expression.
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fig02: The ‘dose of activation’ view of TFBS action and the emergence of redundancy. A: The probabilistic model of transcriptional initiation involving transient ‘hit-and-run’ interactions (Fig. 1) suggests that TF-binding events at multiple TFBSs provide generally cumulative inputs (‘doses of activation’) to their target promoters. B: When the total input from a group of TFBSs narrowly reaches the minimum tolerable ‘dose’, mutations at individual TFBSs will be poorly tolerated. C: If, on the other hand, the total inputs exceed this dose, the system becomes partially redundant and mutations at individual TFBSs may not cause significant changes in gene expression.

Mentions: Let us consider a hypothetical gene promoter that receives inputs from several TFBSs (Fig. 2A). If the total ‘dose of activation’ jointly transmitted to it narrowly reaches the biologically admissible threshold, each TFBS is likely to be deemed ‘functional’ in perturbation analyses, as its deletion will result in a ‘dose’ insufficient for achieving the minimally functional level of a gene's expression (Fig. 2B). However, if their total contribution exceeds this threshold, at least under some conditions, the system becomes partially redundant, rendering the transcriptional output relatively insensitive to perturbations at individual TFBSs (Fig. 2C). Here, I will consider the likely causes and consequences of such redundancy.


Spurious transcription factor binding: non-functional or genetically redundant?

Spivakov M - Bioessays (2014)

The ‘dose of activation’ view of TFBS action and the emergence of redundancy. A: The probabilistic model of transcriptional initiation involving transient ‘hit-and-run’ interactions (Fig. 1) suggests that TF-binding events at multiple TFBSs provide generally cumulative inputs (‘doses of activation’) to their target promoters. B: When the total input from a group of TFBSs narrowly reaches the minimum tolerable ‘dose’, mutations at individual TFBSs will be poorly tolerated. C: If, on the other hand, the total inputs exceed this dose, the system becomes partially redundant and mutations at individual TFBSs may not cause significant changes in gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230394&req=5

fig02: The ‘dose of activation’ view of TFBS action and the emergence of redundancy. A: The probabilistic model of transcriptional initiation involving transient ‘hit-and-run’ interactions (Fig. 1) suggests that TF-binding events at multiple TFBSs provide generally cumulative inputs (‘doses of activation’) to their target promoters. B: When the total input from a group of TFBSs narrowly reaches the minimum tolerable ‘dose’, mutations at individual TFBSs will be poorly tolerated. C: If, on the other hand, the total inputs exceed this dose, the system becomes partially redundant and mutations at individual TFBSs may not cause significant changes in gene expression.
Mentions: Let us consider a hypothetical gene promoter that receives inputs from several TFBSs (Fig. 2A). If the total ‘dose of activation’ jointly transmitted to it narrowly reaches the biologically admissible threshold, each TFBS is likely to be deemed ‘functional’ in perturbation analyses, as its deletion will result in a ‘dose’ insufficient for achieving the minimally functional level of a gene's expression (Fig. 2B). However, if their total contribution exceeds this threshold, at least under some conditions, the system becomes partially redundant, rendering the transcriptional output relatively insensitive to perturbations at individual TFBSs (Fig. 2C). Here, I will consider the likely causes and consequences of such redundancy.

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.

View Article: PubMed Central - PubMed

Affiliation: Babraham Institute, Cambridge, UK.

Show MeSH
Related in: MedlinePlus