4.8 Article

Specificity of the Hox member Deformed is determined by transcription factor levels and binding site affinities

Journal

NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32408-8

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Funding

  1. Deutsche Forschungsgemeinschaft
  2. Heidelberg University

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Hox proteins have similar binding specificities in vitro but control different morphologies in vivo. This paradox has been partially resolved with the discovery of low-affinity binding sites. The specificity of anterior Hox proteins, which are more promiscuous than posterior Hox proteins, is achieved through a precise balance of transcription factors and binding site affinities. Small variations in affinity change the enhancer's sensitivity to different Hox levels, resulting in perturbed gene expression and morphogenesis.
Hox proteins have similar binding specificities in vitro, yet they control different morphologies in vivo. This paradox has been partially solved with the identification of Hox low-affinity binding sites. However, anterior Hox proteins are more promiscuous than posterior Hox proteins, raising the question how anterior Hox proteins achieve specificity. We use the AP2x enhancer, which is activated in the maxillary head segment by the Hox TF Deformed (Dfd). This enhancer lacks canonical Dfd-Exd sites but contains several predicted low-affinity sites. Unexpectedly, these sites are strongly bound by Dfd-Exd complexes and their conversion into optimal Dfd-Exd sites results only in a modest increase in binding strength. These small variations in affinity change the sensitivity of the enhancer to different Dfd levels, resulting in perturbed AP-2 expression and maxillary morphogenesis. Thus, Hox-regulated morphogenesis seems to result from the co-evolution of Hox binding affinity and Hox dosage for precise target gene regulation. Despite the central role of Hox genes in controlling morphogenesis, the DNA binding of different Hox members is relatively similar. Here they show that specificity of Hox member Dfd relies on a precise balance of transcription factors and binding site affinities.

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