DNA Microarray Analyses of Circadian Timing: The Genomic Basis of Biological Time

Abstract

Many aspects of physiology and behaviour are organized around a daily rhythm, driven by an endogenous circadian clock. Studies across numerous taxa have identified interlocked autoregulatory molecular feedback loops which underlie circadian organization in single cells. Until recently, little was known of (i) how the core clock mechanism regulates circadian output and (ii) what proportion of the cellular transcriptome is clock regulated. Studies using DNA microarray technology have addressed these questions in a global fashion and identified rhythmically expressed genes in numerous tissues in the rodent (suprachiasmatic nucleus, pineal gland, liver, heart, kidney) and immortalized fibroblasts, in the head and body of Drosophila, in the fungus Neurospora and the higher plant Arabidopsis. These clock controlled genes represent 0.5-9% of probed genes, with functional groups covering a broad spectrum of cellular pathways. There is considerable tissue specificity, with only approximately 10% rhythmic genes common to at least one other tissue, principally consisting of known clock genes. The remaining common genes may constitute genes operating close to the clock mechanism or novel core clock components. Microarray technology has also been applied to understand input pathways to the clock, identifying potential signalling components for clock resetting in fibroblasts, and elucidating the temperature entrainment mechanism in Neurospora. This review explores some of the common themes found between tissues and organisms, and focuses on some of the striking connections between the molecular core oscillator and aspects of circadian physiology and behaviour. It also addresses the limitations of the microarray technology and analyses, and suggests directions for future studies.

Pharmacological modulators of the circadian clock as potential therapeutic drugs

“…In addition to the core components of the molecular oscillator, the CLOCK/BMAL1 complex drives rhythmic transcription of numerous clock-controlled genes either directly via the E-box regulatory element in their promoter region, or indirectly, via the rhythmic control of other transcription factors whose expression is under clock control [10]. The results of global temporal transcriptional profiling of various tissues using a microarray hybridization approach have estimated that as much as 10% of mammalian transcriptome oscillates in a circadian manner [11][12][13].…”

The role of microRNAs (miRNA) in circadian rhythmicity

“…Genomewide expression analysis from several microarray studies in different organisms indicates that the expression of as much as 5%-10% of transcripts in a specific tissue oscillates in a circadian manner (Claridge-Chang et al 2001;McDonald and Rosbash 2001;Akhtar et al 2002;Ceriani et al 2002;Lin et al 2002;Panda et al 2002;Storch et al 2002;Ueda et al 2002;Duffield 2003;Keegan et al 2007). …”

A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock

“…Several accessory feedback loops -one of them involving the nuclear hormone receptors oÉîJÉêÄα (kêNÇN) and oçêα (oçê~) -stabilise this rhythm and provide further means for in-and output to and from the molecular clock (Ko and Takahashi, 2006). The nature of CCGs varies between different tissues, providing a way to translate time information into physiologically meaningful signals (Duffield, 2003).…”