Identification of the REST regulon reveals extensive transposable element-mediated binding site duplication.
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.
Johnson
Rory
R
Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK. bmbrj@leeds.ac.uk
Gamblin
Richard J
RJ
Ooi
Lezanne
L
Bruce
Alexander W
AW
Donaldson
Ian J
IJ
Westhead
David R
DR
Wood
Ian C
IC
Jackson
Richard M
RM
Buckley
Noel J
NJ
D000818:Animals; D001665:Binding Sites; D015220:Calcium Channels / Q000235:genetics; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type / Q000235:genetics; D020907:Calcium Channels, Q-Type / Q000235:genetics; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D051379:Mice; D009154:Mutation; D050436:Regulatory Elements, Transcriptional; D018085:Regulon; D012097:Repressor Proteins / Q000378:metabolism*; D018626:Retroelements; D014157:Transcription Factors / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D012097:Repressor Proteins; D018626:Retroelements; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C105656:CACNA1A protein, human