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Open Access Research article

Ancient Pbx-Hox signatures define hundreds of vertebrate developmental enhancers

Hugo J Parker1, Paul Piccinelli1, Tatjana Sauka-Spengler2, Marianne Bronner3 and Greg Elgar1*

Author Affiliations

1 Division of Systems Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

2 Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK

3 Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA

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BMC Genomics 2011, 12:637  doi:10.1186/1471-2164-12-637

Published: 30 December 2011

Abstract

Background

Gene regulation through cis-regulatory elements plays a crucial role in development and disease. A major aim of the post-genomic era is to be able to read the function of cis-regulatory elements through scrutiny of their DNA sequence. Whilst comparative genomics approaches have identified thousands of putative regulatory elements, our knowledge of their mechanism of action is poor and very little progress has been made in systematically de-coding them.

Results

Here, we identify ancient functional signatures within vertebrate conserved non-coding elements (CNEs) through a combination of phylogenetic footprinting and functional assay, using genomic sequence from the sea lamprey as a reference. We uncover a striking enrichment within vertebrate CNEs for conserved binding-site motifs of the Pbx-Hox hetero-dimer. We further show that these predict reporter gene expression in a segment specific manner in the hindbrain and pharyngeal arches during zebrafish development.

Conclusions

These findings evoke an evolutionary scenario in which many CNEs evolved early in the vertebrate lineage to co-ordinate Hox-dependent gene-regulatory interactions that pattern the vertebrate head. In a broader context, our evolutionary analyses reveal that CNEs are composed of tightly linked transcription-factor binding-sites (TFBSs), which can be systematically identified through phylogenetic footprinting approaches. By placing a large number of ancient vertebrate CNEs into a developmental context, our findings promise to have a significant impact on efforts toward de-coding gene-regulatory elements that underlie vertebrate development, and will facilitate building general models of regulatory element evolution.

Keywords:
Gene regulation; enhancer code; sea lamprey; Hox genes; embryogenesis