This article is part of the supplement: First International Conference on Phylogenomics

Open Access Open Badges Research

Evolution of motif variants and positional bias of the cyclic-AMP response element

Brandon Smith1*, Hung Fang2, Youlian Pan4, P Roy Walker1, A Fazel Famili4 and Marianna Sikorska3

Author Affiliations

1 Neurogenomics Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada

2 Glycosyltransferases and Neuroglycomics Group, Institute for Biological Sciences, National Research Council of Canada Ottawa Ontario, Canada

3 Neurogenesis and Brain Repair Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada

4 Integrated Reasoning Group, Institute for Information Technology, National Research Council of Canada, Ottawa, Ontario, Canada

For all author emails, please log on.

BMC Evolutionary Biology 2007, 7(Suppl 1):S15  doi:10.1186/1471-2148-7-S1-S15

Published: 8 February 2007



Transcription factors regulate gene expression by interacting with their specific DNA binding sites. Some transcription factors, particularly those involved in transcription initiation, always bind close to transcription start sites (TSS). Others have no such preference and are functional on sites even tens of thousands of base pairs (bp) away from the TSS.

The Cyclic-AMP response element (CRE) binding protein (CREB) binds preferentially to a palindromic sequence (TGACGTCA), known as the canonical CRE, and also to other CRE variants. CREB can activate transcription at CREs thousands of bp away from the TSS, but in mammals CREs are found far more frequently within 1 to 150 bp upstream of the TSS than in any other region. This property is termed positional bias.

The strength of CREB binding to DNA is dependent on the sequence of the CRE motif. The central CpG dinucleotide in the canonical CRE (TGACGTCA) is critical for strong binding of CREB dimers. Methylation of the cytosine in the CpG can inhibit binding of CREB. Deamination of the methylated cytosines causes a C to T transition, resulting in a functional, but lower affinity CRE variant, TGATGTCA.


We performed genome-wide surveys of CREs in a number of species (from worm to human) and showed that only vertebrates exhibited a CRE positional bias. We performed pair-wise comparisons of human CREs with orthologous sequences in mouse, rat and dog genomes and found that canonical and TGATGTCA variant CREs are highly conserved in mammals. However, when orthologous sequences differ, canonical CREs in human are most frequently TGATGTCA in the other species and vice-versa. We have identified 207 human CREs showing such differences.


Our data suggest that the positional bias of CREs likely evolved after the separation of urochordata and vertebrata. Although many canonical CREs are conserved among mammals, there are a number of orthologous genes that have canonical CREs in one species but the TGATGTCA variant in another. These differences are likely due to deamination of the methylated cytosines in the CpG and may contribute to differential transcriptional regulation among orthologous genes.