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 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.
Highlights
Organisms throughout evolution have developed biological clocks to better adapt to the twenty-four hour period of the solar day
We focus our study on transcription factors that are themselves reported as circadian expressed and on factors whose known target genes belong to our list of 2065 clock-controlled genes (CCGs)
We found that promoters of CCGs reported in several DNA-array studies exhibit relatively high GCcontent
Summary
Organisms throughout evolution have developed biological clocks to better adapt to the twenty-four hour period of the solar day. Endogenous circadian oscillations have been observed in a variety of species including cyanobacteria [1,2] and plants [3]. Circadian clocks are self-sustained oscillators that regulate the temporal organisation of physiology, metabolism and behavior [4]. Many aspects of physiology are subject to circadian regulation: sleep-wake cycles and cognitive performance, cardiac and renal functions, digestion and detoxification. About 10% of genes exhibit circadian patterns of expression in a given tissue. The sets of circadian regulated genes differ considerably among tissues [5,6]
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