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Regulation of clock-controlled genes in mammals.

Bozek K, Relógio A, Kielbasa SM, Heine M, Dame C, Kramer A, Herzel H - PLoS ONE (2009)

Bottom Line: We found that many of the transcription factors with overrepresented binding sites in CCG promoters exhibit themselves circadian rhythms.Putative tissue-specific binding sites such as HNF-3 for liver, NKX2.5 for heart or Myogenin for skeletal muscle were found.Results of this study point to connections of the circadian clock to other functional systems including metabolism, endocrine regulation and pharmacokinetics.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Informatics, Saarbrücken, Germany.

ABSTRACT
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 CLOCKratioBMAL1, DBP, HLF, E4BP4, CREB, RORalpha and the recently described regulators HSF1, STAT3, SP1 and HNF-4alpha. 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.

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A putative network of circadian regulation.The figure illustrates our computational predictions nested in other regulatory interactions reported in the literature. Solid line boxes contain transcription factors predicted by our study to regulate clock controlled genes. Dashed line boxes contain other factors involved in the regulation of clock controlled genes as provided by the literature. Transcription factors in bold letters are those reported to be clock controlled by at least one of the microarray studies mentioned in the main text or in other publications [58], [59]. Black arrows indicate activation, red dead-end lines inhibition and blue simple lines represent interaction. References to the literature reporting on particular interactions are indicated next to each connecting line. The full reference list can be found in the supplementary material. Several functional groups are highlighted: core clock proteins in green, proteins related to metabolism and detoxification in red, immune system related proteins in grey and muscle-specific in blue.
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pone-0004882-g006: A putative network of circadian regulation.The figure illustrates our computational predictions nested in other regulatory interactions reported in the literature. Solid line boxes contain transcription factors predicted by our study to regulate clock controlled genes. Dashed line boxes contain other factors involved in the regulation of clock controlled genes as provided by the literature. Transcription factors in bold letters are those reported to be clock controlled by at least one of the microarray studies mentioned in the main text or in other publications [58], [59]. Black arrows indicate activation, red dead-end lines inhibition and blue simple lines represent interaction. References to the literature reporting on particular interactions are indicated next to each connecting line. The full reference list can be found in the supplementary material. Several functional groups are highlighted: core clock proteins in green, proteins related to metabolism and detoxification in red, immune system related proteins in grey and muscle-specific in blue.

Mentions: Even though hormone receptor recognition motifs do not display the highest z-scores, the combined action with other overrepresented transcription factor motifs might play a role in the regulation of many clock-controlled genes. Tronche and others mention the competition of the GR with AP-1, NF-κB, CREB, GATA-1 and OCT-1 as well as its interaction with C/EBPβ or STAT5 in transcriptional regulation [37]. These interactions are shown as part of a large network (Figure 6) involving also others CCGs and core clock genes. The network provides an in-depth analysis of the predicted factors and their interactions with the different functional groups. References supporting the figure are provided in the supplementary Text S3.


Regulation of clock-controlled genes in mammals.

Bozek K, Relógio A, Kielbasa SM, Heine M, Dame C, Kramer A, Herzel H - PLoS ONE (2009)

A putative network of circadian regulation.The figure illustrates our computational predictions nested in other regulatory interactions reported in the literature. Solid line boxes contain transcription factors predicted by our study to regulate clock controlled genes. Dashed line boxes contain other factors involved in the regulation of clock controlled genes as provided by the literature. Transcription factors in bold letters are those reported to be clock controlled by at least one of the microarray studies mentioned in the main text or in other publications [58], [59]. Black arrows indicate activation, red dead-end lines inhibition and blue simple lines represent interaction. References to the literature reporting on particular interactions are indicated next to each connecting line. The full reference list can be found in the supplementary material. Several functional groups are highlighted: core clock proteins in green, proteins related to metabolism and detoxification in red, immune system related proteins in grey and muscle-specific in blue.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654074&req=5

pone-0004882-g006: A putative network of circadian regulation.The figure illustrates our computational predictions nested in other regulatory interactions reported in the literature. Solid line boxes contain transcription factors predicted by our study to regulate clock controlled genes. Dashed line boxes contain other factors involved in the regulation of clock controlled genes as provided by the literature. Transcription factors in bold letters are those reported to be clock controlled by at least one of the microarray studies mentioned in the main text or in other publications [58], [59]. Black arrows indicate activation, red dead-end lines inhibition and blue simple lines represent interaction. References to the literature reporting on particular interactions are indicated next to each connecting line. The full reference list can be found in the supplementary material. Several functional groups are highlighted: core clock proteins in green, proteins related to metabolism and detoxification in red, immune system related proteins in grey and muscle-specific in blue.
Mentions: Even though hormone receptor recognition motifs do not display the highest z-scores, the combined action with other overrepresented transcription factor motifs might play a role in the regulation of many clock-controlled genes. Tronche and others mention the competition of the GR with AP-1, NF-κB, CREB, GATA-1 and OCT-1 as well as its interaction with C/EBPβ or STAT5 in transcriptional regulation [37]. These interactions are shown as part of a large network (Figure 6) involving also others CCGs and core clock genes. The network provides an in-depth analysis of the predicted factors and their interactions with the different functional groups. References supporting the figure are provided in the supplementary Text S3.

Bottom Line: We found that many of the transcription factors with overrepresented binding sites in CCG promoters exhibit themselves circadian rhythms.Putative tissue-specific binding sites such as HNF-3 for liver, NKX2.5 for heart or Myogenin for skeletal muscle were found.Results of this study point to connections of the circadian clock to other functional systems including metabolism, endocrine regulation and pharmacokinetics.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Informatics, Saarbrücken, Germany.

ABSTRACT
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 CLOCKratioBMAL1, DBP, HLF, E4BP4, CREB, RORalpha and the recently described regulators HSF1, STAT3, SP1 and HNF-4alpha. 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.

Show MeSH