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Nucleic Acids Research Advance Access originally published online on August 9, 2006
Nucleic Acids Research 2006 34(14):3862-3877; doi:10.1093/nar/gkl525
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Nucleic Acids Research, 2006, Vol. 34, No. 14 3862-3877
© 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genomics

Identification of the REST regulon reveals extensive transposable element-mediated binding site duplication

Rory Johnson*, Richard J. Gamblin1, Lezanne Ooi, Alexander W. Bruce2, Ian J. Donaldson3, David R. Westhead1, Ian C. Wood, Richard M. Jackson1 and Noel J. Buckley4

Institute of Membrane and Systems Biology, University of Leeds Leeds LS2 9JT, UK 1 Institute of Molecular and Cellular Biology, University of Leeds Leeds LS2 9JT, UK 2 Wellcome Trust Sanger Institute, Hinxton Cambridge CB10 1SA, UK 3 Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge Cambridge CB2 2XY, UK 4 Centre for the Cellular Basis of Behaviour, Centre for Cell & Integrative Biology, Rm 1-045, King’s College London, Institute of Psychiatry 125 Cold Harbour Lane, London SE5 9NU, UK

*To whom correspondence should be addressed. Tel: +44 113 3433015; Fax: +44 113 3433167; Email: bmbrj{at}leeds.ac.uk

Received April 11, 2006. Revised June 1, 2006. Accepted July 10, 2006.

The genome-wide mapping of gene-regulatory motifs remains a major goal that will facilitate the modelling of gene-regulatory networks and their evolution. The repressor element 1 is a long, conserved transcription factor-binding site which recruits the transcriptional repressor REST to numerous neuron-specific target genes. REST plays important roles in multiple biological processes and disease states. To map RE1 sites and target genes, we created a position specific scoring matrix representing the RE1 and used it to search the human and mouse genomes. We identified 1301 and 997 RE1s inhuman and mouse genomes, respectively, of which >40% are novel. By employing an ontological analysis we show that REST target genes are significantly enriched in a number of functional classes. Taking the novel REST target gene CACNA1A as an experimental model, we show that it can be regulated by multiple RE1s of different binding affinities, which are only partially conserved between human and mouse. A novel BLAST methodology indicated that many RE1s belong to closely related families. Most of these sequences are associated with transposable elements, leading us to propose that transposon-mediated duplication and insertion of RE1s has led to the acquisition of novel target genes by REST during evolution.

The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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