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CLOCK-controlled polyphonic regulation of circadian rhythms through canonical and noncanonical E-boxes.
Molecular and Cellular Biology
Date de publication
In mammalian circadian clockwork, the CLOCK-BMAL1 complex binds to DNA enhancers of target genes and drives circadian oscillation of transcription. Here we identified 7,978 CLOCK-binding sites in mouse liver by chromatin immunoprecipitation-sequencing (ChIP-Seq), and a newly developed bioinformatics method, motif centrality analysis of ChIP-Seq (MOCCS), revealed a genome-wide distribution of previously unappreciated noncanonical E-boxes targeted by CLOCK. In vitro promoter assays showed that CACGNG, CACGTT, and CATG(T/C)G are functional CLOCK-binding motifs. Furthermore, we extensively revealed rhythmically expressed genes by poly(A)-tailed RNA-Seq and identified 1,629 CLOCK target genes within 11,926 genes expressed in the liver. Our analysis also revealed rhythmically expressed genes that have no apparent CLOCK-binding site, indicating the importance of indirect transcriptional and posttranscriptional regulations. Indirect transcriptional regulation is represented by rhythmic expression of CLOCK-regulated transcription factors, such as Krüppel-like factors (KLFs). Indirect posttranscriptional regulation involves rhythmic microRNAs that were identified by small-RNA-Seq. Collectively, CLOCK-dependent direct transactivation through multiple E-boxes and indirect regulations polyphonically orchestrate dynamic circadian outputs.
Animals, Base Sequence, Binding Sites, CLOCK Proteins/physiology, Circadian Rhythm, Consensus Sequence, E-Box Elements, HEK293 Cells, Humans, Kruppel-Like Transcription Factors/metabolism, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs/genetics, MicroRNAs/metabolism, Protein Binding, RNA Interference, Transcriptome
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