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Ancient Pbx-Hox signatures define hundreds of vertebrate developmental enhancers

Parker, Hugo J. and Piccinelli, Paul and Sauka-Spengler, Tatjana and Elgar, Greg and Bronner, Marianne E. (2011) Ancient Pbx-Hox signatures define hundreds of vertebrate developmental enhancers. BMC Genomics, 12 . Art. No. 637. ISSN 1471-2164. https://resolver.caltech.edu/CaltechAUTHORS:20120210-094550755

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1186/1471-2164-12-637 DOIUNSPECIFIED
http://www.biomedcentral.com/1471-2164/12/637PublisherUNSPECIFIED
Additional Information:© 2011 Parker et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 7 October 2011; Accepted: 30 December 2011; Published: 30 December 2011. We are indebted to Andrew McCallion and Koichi Kawakami for supplying us with the pGW_cfosEGFP construct, and Reinhard Koester for the r3r5 transgenic zebrafish line. We thank Stefan Pauls and Debbie Goode for helpful suggestions on the manuscript. This work was funded by MRC Project Grant 72504 to GE and NIH Grant DE017911 to MB. HJP was funded by a QMUL PhD studentship. Authors’ contributions: Conceived and designed the experiments: HJP and GE. Performed the experiments: HJP. Conceived and designed bio-informatic analyses: PP, HJP and GE. Performed bio-informatic analyses: PP and GE. Analysed the data: HJP, PP and GE. Supplied materials, reagents and lamprey expertise: MB and TS-S. Wrote the paper: HJP, PP and GE. All authors read and approved the final manuscript.
Funders:
Funding AgencyGrant Number
MRC Project Grant72504
NIHDE017911
QMUL PhD studentshipUNSPECIFIED
Subject Keywords:Gene regulation, enhancer code, sea lamprey, Hox genes, embryogenesis
Record Number:CaltechAUTHORS:20120210-094550755
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120210-094550755
Official Citation:Parker et al.: Ancient Pbx-Hox signatures define hundreds of vertebrate developmental enhancers. BMC Genomics 2011 12:637.
Usage Policy:This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ID Code:29232
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Mar 2012 20:41
Last Modified:03 Oct 2019 03:39

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