Modeling an evolutionary conserved circadian cis-element.
Circadian oscillator networks rely on a transcriptional activator called CLOCK/CYCLE (CLK/CYC) in insects and CLOCK/BMAL1 or NPAS2/BMAL1 in mammals. Identifying the targets of this heterodimeric basic-helix-loop-helix (bHLH) transcription factor poses challenges and it has been difficult to decipher...
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Public Library of Science (PLoS)
2008-02-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.0040038&type=printable |
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| author | Eric R Paquet Guillaume Rey Felix Naef |
| author_facet | Eric R Paquet Guillaume Rey Felix Naef |
| author_sort | Eric R Paquet |
| collection | DOAJ |
| description | Circadian oscillator networks rely on a transcriptional activator called CLOCK/CYCLE (CLK/CYC) in insects and CLOCK/BMAL1 or NPAS2/BMAL1 in mammals. Identifying the targets of this heterodimeric basic-helix-loop-helix (bHLH) transcription factor poses challenges and it has been difficult to decipher its specific sequence affinity beyond a canonical E-box motif, except perhaps for some flanking bases contributing weakly to the binding energy. Thus, no good computational model presently exists for predicting CLK/CYC, CLOCK/BMAL1, or NPAS2/BMAL1 targets. Here, we use a comparative genomics approach and first study the conservation properties of the best-known circadian enhancer: a 69-bp element upstream of the Drosophila melanogaster period gene. This fragment shows a signal involving the presence of two closely spaced E-box-like motifs, a configuration that we can also detect in the other four prominent CLK/CYC target genes in flies: timeless, vrille, Pdp1, and cwo. This allows for the training of a probabilistic sequence model that we test using functional genomics datasets. We find that the predicted sequences are overrepresented in promoters of genes induced in a recent study by a glucocorticoid receptor-CLK fusion protein. We then scanned the mouse genome with the fly model and found that many known CLOCK/BMAL1 targets harbor sequences matching our consensus. Moreover, the phase of predicted cyclers in liver agreed with known CLOCK/BMAL1 regulation. Taken together, we built a predictive model for CLK/CYC or CLOCK/BMAL1-bound cis-enhancers through the integration of comparative and functional genomics data. Finally, a deeper phylogenetic analysis reveals that the link between the CLOCK/BMAL1 complex and the circadian cis-element dates back to before insects and vertebrates diverged. |
| format | Article |
| id | doaj-art-4879e187d2dd4cf59d66f57d4f9c2799 |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2008-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-4879e187d2dd4cf59d66f57d4f9c27992025-08-20T02:00:55ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582008-02-0142e3810.1371/journal.pcbi.0040038Modeling an evolutionary conserved circadian cis-element.Eric R PaquetGuillaume ReyFelix NaefCircadian oscillator networks rely on a transcriptional activator called CLOCK/CYCLE (CLK/CYC) in insects and CLOCK/BMAL1 or NPAS2/BMAL1 in mammals. Identifying the targets of this heterodimeric basic-helix-loop-helix (bHLH) transcription factor poses challenges and it has been difficult to decipher its specific sequence affinity beyond a canonical E-box motif, except perhaps for some flanking bases contributing weakly to the binding energy. Thus, no good computational model presently exists for predicting CLK/CYC, CLOCK/BMAL1, or NPAS2/BMAL1 targets. Here, we use a comparative genomics approach and first study the conservation properties of the best-known circadian enhancer: a 69-bp element upstream of the Drosophila melanogaster period gene. This fragment shows a signal involving the presence of two closely spaced E-box-like motifs, a configuration that we can also detect in the other four prominent CLK/CYC target genes in flies: timeless, vrille, Pdp1, and cwo. This allows for the training of a probabilistic sequence model that we test using functional genomics datasets. We find that the predicted sequences are overrepresented in promoters of genes induced in a recent study by a glucocorticoid receptor-CLK fusion protein. We then scanned the mouse genome with the fly model and found that many known CLOCK/BMAL1 targets harbor sequences matching our consensus. Moreover, the phase of predicted cyclers in liver agreed with known CLOCK/BMAL1 regulation. Taken together, we built a predictive model for CLK/CYC or CLOCK/BMAL1-bound cis-enhancers through the integration of comparative and functional genomics data. Finally, a deeper phylogenetic analysis reveals that the link between the CLOCK/BMAL1 complex and the circadian cis-element dates back to before insects and vertebrates diverged.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.0040038&type=printable |
| spellingShingle | Eric R Paquet Guillaume Rey Felix Naef Modeling an evolutionary conserved circadian cis-element. PLoS Computational Biology |
| title | Modeling an evolutionary conserved circadian cis-element. |
| title_full | Modeling an evolutionary conserved circadian cis-element. |
| title_fullStr | Modeling an evolutionary conserved circadian cis-element. |
| title_full_unstemmed | Modeling an evolutionary conserved circadian cis-element. |
| title_short | Modeling an evolutionary conserved circadian cis-element. |
| title_sort | modeling an evolutionary conserved circadian cis element |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.0040038&type=printable |
| work_keys_str_mv | AT ericrpaquet modelinganevolutionaryconservedcircadianciselement AT guillaumerey modelinganevolutionaryconservedcircadianciselement AT felixnaef modelinganevolutionaryconservedcircadianciselement |