Abstract
Circadian clocks are endogenous oscillators driving daily rhythms in physiology. The cell-autonomous clock is governed by an interlocked network of transcriptional feedback loops. Hundreds of clock-controlled genes (CCGs) regulate tissue specific functions. Transcriptome studies reveal that different organs (e.g. liver, heart, adrenal gland) feature substantially varying sets of CCGs with different peak phase distributions. To study the phase variability of CCGs in mammalian peripheral tissues, we develop a core clock model for mouse liver and adrenal gland based on expression profiles and known cis-regulatory sites. ‘Modulation factors’ associated with E-boxes, ROR-elements, and D-boxes can explain variable rhythms of CCGs, which is demonstrated for differential regulation of cytochromes P450 and 12 h harmonics. By varying model parameters we explore how tissue-specific peak phase distributions can be generated. The central role of E-boxes and ROR-elements is confirmed by analysing ChIP-seq data of BMAL1 and REV-ERB transcription factors.
Highlights
Circadian clocks are endogenous oscillators driving daily rhythms in physiology
To study the phase variability of clock-controlled genes (CCGs) in mammalian peripheral tissues, we develop a core clock model for mouse liver and adrenal gland based on expression profiles and known cis-regulatory sites
We explore the regulation of CCGs by comparing expression profiles in mouse liver and adrenal glands
Summary
Circadian clocks are endogenous oscillators driving daily rhythms in physiology. The cell-autonomous clock is governed by an interlocked network of transcriptional feedback loops. To study the phase variability of CCGs in mammalian peripheral tissues, we develop a core clock model for mouse liver and adrenal gland based on expression profiles and known cis-regulatory sites. Up to 10% of all mammalian genes oscillate in their expression levels with a period of about 24 h3,4 These clock-controlled genes (CCGs) modulate essential physiological processes in an optimized tissue-specific manner. We explore the regulation of CCGs by comparing expression profiles in mouse liver and adrenal glands For both tissues we analyse our own data for core clock genes from light-dark (LD) cycles and constant darkness (DD). Using carefully normalized expression profiles together with experimentally verified circadian cis-regulatory elements we derive for both tissues and both conditions a gene regulatory model of the core clock. We show that multiplicative regulation by core clock components can generate harmonics
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