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Gene regulation

Landscape and mechanisms of transcription factor cooperativity

Nature Reviews Genetics volume 17, page 5 (2016)Cite this article

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Stampfel et al. developed enhancer complementation assays to investigate the regulatory effects of different TFs and cofactors after DNA binding. The researchers constructed fusion proteins in which TFs or transcriptional cofactors were coupled to the GAL4 DNA-binding domain. They also created different 'enhancer contexts' in Drosophila melanogaster S2 cells by replacing individual DNA-binding motifs in enhancer sequences with the upstream activating sequence (UAS), which is bound by the GAL4 DNA-binding domain. The transcriptional effects of different TFs and cofactors recruited to these enhancer contexts were then assessed by luciferase assays. In total, the researchers tested 474 TFs and 338 cofactors, each within 24 different enhancer contexts.

Most of the fusion proteins assessed were functional, either repressing or activating gene expression in at least one enhancer context. The researchers categorized the TFs into 15 clusters on the basis of similar functional profiles and saw that the TFs within each cluster seemed to be functionally equivalent across various cell types. The team also noted a similarity between the effects of TFs and cofactors of particular functional classes, for example, between globally activating TFs and globally activating cofactors, and between context-dependent TFs and context-dependent cofactors (although, interestingly, globally repressing TFs form three distinct clusters that appear to function via different cofactors). These similarities in regulatory function enabled Stampfel et al. to predict TF–cofactor pairs. The fact that some of these pairs are known to physically interact supports the idea that these correspondences are true functional associations, which the authors validated with additional functional assays.

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References

  1. Stampfel, G. et al. Transcriptional regulators form diverse groups with context-dependent regulatory functions. Nature http://dx.doi.org/10.1038/nature15545 (2015)

  2. Jolma, A. et al. DNA-dependent formation of transcriptional factor pairs alters their binding specificity. Nature http://dx.doi.org/10.1038/nature15518 (2015)

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Authors
  1. Joana Osório
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Osório, J. Landscape and mechanisms of transcription factor cooperativity. Nat Rev Genet 17, 5 (2016). https://doi.org/10.1038/nrg.2015.11

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