MPI für molekulare Genetik / Department of Computational Molecular Biology |
|Regulation of Clock-Controlled Genes in Mammals.|
|Authors:||Bozek, Katarzyna; Relógio, Angela; Kielbasa, Szymon M.; Heine, Markus; Dame, Christof; Kramer, Achim; Herzel, Hanspeter|
|Research Context:||The Deutsche Forschungsgemeinschaft (SFB 618) and the EU (BIOSIM network) are acknowledged for financial support. Research in A.K.'s lab is supported by the 6th European Framework program EUCLOCK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.|
|Date of Publication (YYYY-MM-DD):||2009-03-16|
|Title of Journal:||PLoS ONE|
|Journal Abbrev.:||PLoS ONE|
|Issue / Number:||3|
|Full name of Issue-Editor(s):||Wyeth W. Wasserman, University of British Columbia, Canada|
|Copyright:||2009 Bozek et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
|Review Status:||not specified|
|Abstract / Description:||The complexity of tissue- and day time-specific regulation of thousands of clock-controlled genes (CCGs) suggests that many regulatory mechanisms contribute to the transcriptional output of the circadian clock. We aim to predict these mechanisms using a large scale promoter analysis of CCGs.
Our study is based on a meta-analysis of DNA-array data from rodent tissues. We searched in the promoter regions of 2065 CCGs for highly overrepresented transcription factor binding sites. In order to compensate the relatively high GC-content of CCG promoters, a novel background model to avoid a bias towards GC-rich motifs was employed. We found that many of the transcription factors with overrepresented binding sites in CCG promoters exhibit themselves circadian rhythms. Among the predicted factors are known regulators such as CLOCK:BMAL1, DBP, HLF, E4BP4, CREB, RORα and the recently described regulators HSF1, STAT3, SP1 and HNF-4α. As additional promising candidates of circadian transcriptional regulators PAX-4, C/EBP, EVI-1, IRF, E2F, AP-1, HIF-1 and NF-Y were identified. Moreover, GC-rich motifs (SP1, EGR, ZF5, AP-2, WT1, NRF-1) and AT-rich motifs (MEF-2, HMGIY, HNF-1, OCT-1) are significantly overrepresented in promoter regions of CCGs. Putative tissue-specific binding sites such as HNF-3 for liver, NKX2.5 for heart or Myogenin for skeletal muscle were found. The regulation of the erythropoietin (Epo) gene was analysed, which exhibits many binding sites for circadian regulators. We provide experimental evidence for its circadian regulated expression in the adult murine kidney. Basing on a comprehensive literature search we integrate our predictions into a regulatory network of core clock and clock-controlled genes. Our large scale analysis of the CCG promoters reveals the complexity and extensiveness of the circadian regulation in mammals. Results of this study point to connections of the circadian clock to other functional systems including metabolism, endocrine regulation and pharmacokinetics.
|Comment of the Author/Creator:||E-mail: email@example.com|
|External Publication Status:||published|
|Communicated by:||Martin Vingron|
|Affiliations:||MPI für molekulare Genetik|
MPI für Informatik/Computational Biology and Applied Algorithmics
|External Affiliations:||1.Institute for Theoretical Biology, Humboldt University, Berlin, Germany;
2.Laboratory of Chronobiology, Charité - Universitäsmedizin Berlin, Berlin, Germany;
3.Department of Neonatology, Campus Virchow-Klinikum Charité - Universitätsmedizin Berlin, Berlin, Germany.
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