Evolution of motif variants and positional bias of the cyclic-AMP response element
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2007-02-01
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| Series: | BMC Evolutionary Biology |
| _version_ | 1818977554378260480 |
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| author | Famili A Fazel Walker P Roy Pan Youlian Fang Hung Smith Brandon Sikorska Marianna |
| author_facet | Famili A Fazel Walker P Roy Pan Youlian Fang Hung Smith Brandon Sikorska Marianna |
| author_sort | Famili A Fazel |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>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.</p> <p>The strength of CREB binding to DNA is dependent on the sequence of the CRE motif. The central CpG dinucleotide in the canonical CRE (TGA<b>CG</b>TCA) 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, TGA<b>T</b>GTCA.</p> <p>Results</p> <p>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 TGA<b>T</b>GTCA variant CREs are highly conserved in mammals. However, when orthologous sequences differ, canonical CREs in human are most frequently TGA<b>T</b>GTCA in the other species and vice-versa. We have identified 207 human CREs showing such differences.</p> <p>Conclusion</p> <p>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 TGA<b>T</b>GTCA 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.</p> |
| first_indexed | 2024-12-20T16:29:35Z |
| format | Article |
| id | doaj.art-b1fda7dae7434efa9dc28f89558bdc37 |
| institution | Directory Open Access Journal |
| issn | 1471-2148 |
| language | English |
| last_indexed | 2024-12-20T16:29:35Z |
| publishDate | 2007-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Evolutionary Biology |
| spelling | doaj.art-b1fda7dae7434efa9dc28f89558bdc372022-12-21T19:33:17ZengBMCBMC Evolutionary Biology1471-21482007-02-017Suppl 1S1510.1186/1471-2148-7-S1-S15Evolution of motif variants and positional bias of the cyclic-AMP response elementFamili A FazelWalker P RoyPan YoulianFang HungSmith BrandonSikorska Marianna<p>Abstract</p> <p>Background</p> <p>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.</p> <p>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.</p> <p>The strength of CREB binding to DNA is dependent on the sequence of the CRE motif. The central CpG dinucleotide in the canonical CRE (TGA<b>CG</b>TCA) 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, TGA<b>T</b>GTCA.</p> <p>Results</p> <p>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 TGA<b>T</b>GTCA variant CREs are highly conserved in mammals. However, when orthologous sequences differ, canonical CREs in human are most frequently TGA<b>T</b>GTCA in the other species and vice-versa. We have identified 207 human CREs showing such differences.</p> <p>Conclusion</p> <p>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 TGA<b>T</b>GTCA 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.</p> |
| spellingShingle | Famili A Fazel Walker P Roy Pan Youlian Fang Hung Smith Brandon Sikorska Marianna Evolution of motif variants and positional bias of the cyclic-AMP response element BMC Evolutionary Biology |
| title | Evolution of motif variants and positional bias of the cyclic-AMP response element |
| title_full | Evolution of motif variants and positional bias of the cyclic-AMP response element |
| title_fullStr | Evolution of motif variants and positional bias of the cyclic-AMP response element |
| title_full_unstemmed | Evolution of motif variants and positional bias of the cyclic-AMP response element |
| title_short | Evolution of motif variants and positional bias of the cyclic-AMP response element |
| title_sort | evolution of motif variants and positional bias of the cyclic amp response element |
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