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Cell. 2015 Jan 15;160(1-2):191-203. doi: 10.1016/j.cell.2014.11.041. Epub 2014 Dec 31.

Low affinity binding site clusters confer hox specificity and regulatory robustness.

Author information

1
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
2
Columbia University Medical Center, 701 West 168(th) Street, HHSC 1104, New York, NY 10032, USA.
3
Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Oxford OX3 0BP, UK.
4
Departamento de Ecología, Genética y Evolución, IEGEBA-CONICET, Facultad, de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad, Universitaria, Pabellón 2, 1428 Buenos Aires, Argentina.
5
New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820, USA.
6
Centre de Biologie du Développement, Université de Toulouse, UPS, 31062 Cedex 9, France; CNRS, UMR5547, Centre de Biologie du Développement, Toulouse, 31062 Cedex 9, France.
7
Columbia University Medical Center, 701 West 168(th) Street, HHSC 1104, New York, NY 10032, USA. Electronic address: rsm10@columbia.edu.
8
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA. Electronic address: sternd@janelia.hhmi.org.

Abstract

In animals, Hox transcription factors define regional identity in distinct anatomical domains. How Hox genes encode this specificity is a paradox, because different Hox proteins bind with high affinity in vitro to similar DNA sequences. Here, we demonstrate that the Hox protein Ultrabithorax (Ubx) in complex with its cofactor Extradenticle (Exd) bound specifically to clusters of very low affinity sites in enhancers of the shavenbaby gene of Drosophila. These low affinity sites conferred specificity for Ubx binding in vivo, but multiple clustered sites were required for robust expression when embryos developed in variable environments. Although most individual Ubx binding sites are not evolutionarily conserved, the overall enhancer architecture-clusters of low affinity binding sites-is maintained and required for enhancer function. Natural selection therefore works at the level of the enhancer, requiring a particular density of low affinity Ubx sites to confer both specific and robust expression.

PMID:
25557079
PMCID:
PMC4449256
DOI:
10.1016/j.cell.2014.11.041
[Indexed for MEDLINE]
Free PMC Article

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