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

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  • Pedro B. Pinto

    (Centre for Organismal Studies (COS) Heidelberg
    Universite Claude Bernard Lyon 1)

  • Katrin Domsch

    (Centre for Organismal Studies (COS) Heidelberg)

  • Xuefan Gao

    (Centre for Organismal Studies (COS) Heidelberg)

  • Michaela Wölk

    (Centre for Organismal Studies (COS) Heidelberg
    Friedrich Miescher Institute for Biomedical Research (FMI))

  • Julie Carnesecchi

    (Centre for Organismal Studies (COS) Heidelberg
    Universite Claude Bernard Lyon 1)

  • Ingrid Lohmann

    (Centre for Organismal Studies (COS) Heidelberg)

Abstract

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.

Suggested Citation

  • Pedro B. Pinto & Katrin Domsch & Xuefan Gao & Michaela Wölk & Julie Carnesecchi & Ingrid Lohmann, 2022. "Specificity of the Hox member Deformed is determined by transcription factor levels and binding site affinities," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32408-8
    DOI: 10.1038/s41467-022-32408-8
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    1. Siqian Feng & Chaitanya Rastogi & Ryan Loker & William J. Glassford & H. Tomas Rube & Harmen J. Bussemaker & Richard S. Mann, 2022. "Transcription factor paralogs orchestrate alternative gene regulatory networks by context-dependent cooperation with multiple cofactors," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
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