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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 ‘hit and run’ model of transcriptional activation. Under this model, transient interactions between transcription factors (TFs) and their binding sites on the DNA (TFBSs) promote the recruitment of chromatin remodellers, core transcriptional co-factors and the RNA polymerase (RNAP). These complexes, also transient in nature, stochastically ‘hit’ promoter regions, resulting in transcriptional initiation. The exact identity of both the TFs themselves and the co-factors they recruit need not be the same in each case, as emphasised by their different colours at the TFBSs ‘upstream’ and ‘downstream’ of the promoter. This model, based on evidence from time-course ChIP and FRAP 28–32, provides a mechanistic explanation of how multiple probabilistic events in gene regulation can lead to deterministic outcomes. TFBSs are depicted to localise some distance away from the promoter, but this model likely also applies to TFBSs located directly at the promoter region. For simplicity, RNAP and core co-factors are shown as freely distributed in the nuclear environment. There is however evidence to suggest that they are enriched at specific nuclear foci termed ‘transcription factories’ 24,25.
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fig01: The ‘hit and run’ model of transcriptional activation. Under this model, transient interactions between transcription factors (TFs) and their binding sites on the DNA (TFBSs) promote the recruitment of chromatin remodellers, core transcriptional co-factors and the RNA polymerase (RNAP). These complexes, also transient in nature, stochastically ‘hit’ promoter regions, resulting in transcriptional initiation. The exact identity of both the TFs themselves and the co-factors they recruit need not be the same in each case, as emphasised by their different colours at the TFBSs ‘upstream’ and ‘downstream’ of the promoter. This model, based on evidence from time-course ChIP and FRAP 28–32, provides a mechanistic explanation of how multiple probabilistic events in gene regulation can lead to deterministic outcomes. TFBSs are depicted to localise some distance away from the promoter, but this model likely also applies to TFBSs located directly at the promoter region. For simplicity, RNAP and core co-factors are shown as freely distributed in the nuclear environment. There is however evidence to suggest that they are enriched at specific nuclear foci termed ‘transcription factories’ 24,25.

Mentions: Understanding the mechanics of transcriptional activation is complicated by the startling diversity of core co-factors involved in this process. For example, the human genome contains four families of ATP-dependent chromatin remodelling complexes, at least four families of histone acetyltransferases, and a multitude of histone modifying enzymes such as methyltransferases and ubiquitin ligases that selectively modify specific histone amino acid residues 26. The early ‘deterministic’ models of transcriptional activation that postulated the existence of a well-orchestrated sequence of events involving ready-to-use core holoenzymes 27 made it difficult to accommodate this diversity of components. Indeed, deterministic models would presume the presence of a near-infinite number of highly specialised holoenzyme complexes, each of which is selectively required for the activation of specific subsets of genes under specific conditions. This deterministic view has however been challenged by studies that directly monitored the sequence of events underlying transcriptional activation in mammalian systems using techniques such as time-course immunoprecipitation 28 and fluorescent recovery after photobleaching (FRAP) 29,30. These analyses revealed that the well-defined deterministic stages of this process (such as chromatin remodelling, pre-initiation complex assembly, and transcriptional initiation) are likely to each comprise a series of transient ‘hit-and-run’ interactions of multiple proteins with each other and the DNA. The exact identity of these interactions and their order of action is flexible and to a degree stochastic 28–32 (Fig. 1).


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

Spivakov M - Bioessays (2014)

The ‘hit and run’ model of transcriptional activation. Under this model, transient interactions between transcription factors (TFs) and their binding sites on the DNA (TFBSs) promote the recruitment of chromatin remodellers, core transcriptional co-factors and the RNA polymerase (RNAP). These complexes, also transient in nature, stochastically ‘hit’ promoter regions, resulting in transcriptional initiation. The exact identity of both the TFs themselves and the co-factors they recruit need not be the same in each case, as emphasised by their different colours at the TFBSs ‘upstream’ and ‘downstream’ of the promoter. This model, based on evidence from time-course ChIP and FRAP 28–32, provides a mechanistic explanation of how multiple probabilistic events in gene regulation can lead to deterministic outcomes. TFBSs are depicted to localise some distance away from the promoter, but this model likely also applies to TFBSs located directly at the promoter region. For simplicity, RNAP and core co-factors are shown as freely distributed in the nuclear environment. There is however evidence to suggest that they are enriched at specific nuclear foci termed ‘transcription factories’ 24,25.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: The ‘hit and run’ model of transcriptional activation. Under this model, transient interactions between transcription factors (TFs) and their binding sites on the DNA (TFBSs) promote the recruitment of chromatin remodellers, core transcriptional co-factors and the RNA polymerase (RNAP). These complexes, also transient in nature, stochastically ‘hit’ promoter regions, resulting in transcriptional initiation. The exact identity of both the TFs themselves and the co-factors they recruit need not be the same in each case, as emphasised by their different colours at the TFBSs ‘upstream’ and ‘downstream’ of the promoter. This model, based on evidence from time-course ChIP and FRAP 28–32, provides a mechanistic explanation of how multiple probabilistic events in gene regulation can lead to deterministic outcomes. TFBSs are depicted to localise some distance away from the promoter, but this model likely also applies to TFBSs located directly at the promoter region. For simplicity, RNAP and core co-factors are shown as freely distributed in the nuclear environment. There is however evidence to suggest that they are enriched at specific nuclear foci termed ‘transcription factories’ 24,25.
Mentions: Understanding the mechanics of transcriptional activation is complicated by the startling diversity of core co-factors involved in this process. For example, the human genome contains four families of ATP-dependent chromatin remodelling complexes, at least four families of histone acetyltransferases, and a multitude of histone modifying enzymes such as methyltransferases and ubiquitin ligases that selectively modify specific histone amino acid residues 26. The early ‘deterministic’ models of transcriptional activation that postulated the existence of a well-orchestrated sequence of events involving ready-to-use core holoenzymes 27 made it difficult to accommodate this diversity of components. Indeed, deterministic models would presume the presence of a near-infinite number of highly specialised holoenzyme complexes, each of which is selectively required for the activation of specific subsets of genes under specific conditions. This deterministic view has however been challenged by studies that directly monitored the sequence of events underlying transcriptional activation in mammalian systems using techniques such as time-course immunoprecipitation 28 and fluorescent recovery after photobleaching (FRAP) 29,30. These analyses revealed that the well-defined deterministic stages of this process (such as chromatin remodelling, pre-initiation complex assembly, and transcriptional initiation) are likely to each comprise a series of transient ‘hit-and-run’ interactions of multiple proteins with each other and the DNA. The exact identity of these interactions and their order of action is flexible and to a degree stochastic 28–32 (Fig. 1).

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