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: 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).