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

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.

[1]  K. Nagai,et al.  Role of SCN in daily rhythms of plasma glucose, FFA, insulin and glucagon. , 1987, Chronobiology international.

[2]  S. Golden,et al.  Circadian orchestration of gene expression in cyanobacteria. , 1995, Genes & development.

[3]  D. Bell-Pedersen,et al.  Circadian clock-controlled genes isolated from Neurospora crassa are late night- to early morning-specific. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Besharse,et al.  Use of a high stringency differential display screen for identification of retinal mRNAs that are regulated by a circadian clock. , 1996, Brain research. Molecular brain research.

[5]  M. Rosbash,et al.  A new gene encoding a putative transcription factor regulated by the Drosophila circadian clock , 1997, The EMBO journal.

[6]  B. Lemmer,et al.  Physiology and Pharmacology of Biological Rhythms , 1997, Handbook of Experimental Pharmacology.

[7]  U. Schibler,et al.  A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells , 1998, Cell.

[8]  M. Rosbash,et al.  Why the Rat-1 Fibroblast Should Replace the SCN as the In Vitro Model of Choice , 1998, Cell.

[9]  S. Kuhlman,et al.  A screen for genes induced in the suprachiasmatic nucleus by light. , 1998, Science.

[10]  M. Bittner,et al.  Expression profiling using cDNA microarrays , 1999, Nature Genetics.

[11]  Till Roenneberg,et al.  Assignment of circadian function for the Neurospora clock gene frequency , 1999, Nature.

[12]  J. Dunlap Molecular Bases for Circadian Clocks , 1999, Cell.

[13]  H. Heller,et al.  Circadian Rhythms in the Suprachiasmatic Nucleus are Temperature-Compensated and Phase-Shifted by Heat Pulses In Vitro , 1999, The Journal of Neuroscience.

[14]  M. Jackson,et al.  Gene expression profiles of laser-captured adjacent neuronal subtypes , 1999, Nature Medicine.

[15]  V. Orlando,et al.  Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation. , 2000, Trends in biochemical sciences.

[16]  John J. Wyrick,et al.  Genome-wide location and function of DNA binding proteins. , 2000, Science.

[17]  Y Sakaki,et al.  Resetting central and peripheral circadian oscillators in transgenic rats. , 2000, Science.

[18]  J. Dunlap,et al.  Interconnected feedback loops in the Neurospora circadian system. , 2000, Science.

[19]  C. Allis,et al.  Light induces chromatin modification in cells of the mammalian circadian clock , 2000, Nature Neuroscience.

[20]  S. Kay,et al.  Orchestrated transcription of key pathways in Arabidopsis by the circadian clock. , 2000, Science.

[21]  Robert J. Schaffer,et al.  Microarray Analysis of Diurnal and Circadian-Regulated Genes in Arabidopsis , 2001, The Plant Cell.

[22]  F. Fleury-Olela,et al.  Analysis of circadian liver gene expression by ADDER, a highly sensitive method for the display of differentially expressed mRNAs. , 2001, Nucleic acids research.

[23]  V. Laudet,et al.  Circadian Regulation of Diverse Gene Products Revealed by mRNA Expression Profiling of Synchronized Fibroblasts* 210 , 2001, The Journal of Biological Chemistry.

[24]  Adam Claridge‐Chang,et al.  Circadian Regulation of Gene Expression Systems in the Drosophila Head , 2001, Neuron.

[25]  S. Reppert,et al.  Molecular analysis of mammalian circadian rhythms. , 2001, Annual review of physiology.

[26]  P. Nelson,et al.  Project normal: Defining normal variance in mouse gene expression , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S. Kay,et al.  Molecular bases of circadian rhythms. , 2001, Annual review of cell and developmental biology.

[28]  Michael J. McDonald,et al.  Microarray Analysis and Organization of Circadian Gene Expression in Drosophila , 2001, Cell.

[29]  Josephine Arendt,et al.  Health in a 24-h society , 2001, The Lancet.

[30]  Steven M. Reppert,et al.  Posttranslational Mechanisms Regulate the Mammalian Circadian Clock , 2001, Cell.

[31]  Jonathan Knight,et al.  When the chips are down , 2001, Nature.

[32]  Christopher R. Jones,et al.  An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome , 2001, Science.

[33]  F. Tamanini,et al.  Molecular Mechanisms of the Biological Clock in Cultured Fibroblasts , 2001, Science.

[34]  P. Etter,et al.  The ups and downs of daily life: profiling circadian gene expression in Drosophila. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[35]  H. Jacob,et al.  Implications of circadian gene expression in kidney, liver and the effects of fasting on pharmacogenomic studies. , 2002, Pharmacogenetics.

[36]  R. Akhtar,et al.  Circadian Cycling of the Mouse Liver Transcriptome, as Revealed by cDNA Microarray, Is Driven by the Suprachiasmatic Nucleus , 2002, Current Biology.

[37]  A. Balsalobre,et al.  Clock genes in mammalian peripheral tissues , 2002, Cell and Tissue Research.

[38]  Peng Huang,et al.  The Circadian Gene Period2 Plays an Important Role in Tumor Suppression and DNA Damage Response In Vivo , 2002, Cell.

[39]  R. Baler,et al.  cDNA Array Analysis of Pineal Gene Expression Reveals Circadian Rhythmicity of the Dominant Negative Helix‐Loop‐Helix Protein‐Encoding Gene, Id‐1 , 2002, Journal of neuroendocrinology.

[40]  Kai-Florian Storch,et al.  Extensive and divergent circadian gene expression in liver and heart , 2002, Nature.

[41]  Jennifer J. Loros,et al.  Circadian Programs of Transcriptional Activation, Signaling, and Protein Turnover Revealed by Microarray Analysis of Mammalian Cells , 2002, Current Biology.

[42]  Y. Fukada,et al.  Light-Dependent Changes in the Chick Pineal Temperature and the Expression of cHsp90 α gene: A Potential Contribution of in vivo Temperature Change to the Photic-Entrainment of the Chick Pineal Circadian Clock , 2002, Zoological science.

[43]  R. Nadon,et al.  Statistical issues with microarrays: processing and analysis. , 2002, Trends in genetics : TIG.

[44]  Jeffrey C. Hall,et al.  Identification of circadian-clock-regulated enhancers and genes of Drosophila melanogaster by transposon mobilization and luciferase reporting of cyclical gene expression. , 2002, Genetics.

[45]  S. Kay,et al.  Genome-Wide Expression Analysis in DrosophilaReveals Genes Controlling Circadian Behavior , 2002, The Journal of Neuroscience.

[46]  T. Kawamoto,et al.  Dec1 and Dec2 are regulators of the mammalian molecular clock , 2002, Nature.

[47]  G. Stormo,et al.  Influence of the period-dependent circadian clock on diurnal, circadian, and aperiodic gene expression in Drosophila melanogaster , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Toshiyuki Okano,et al.  Glucose Down-regulates Per1 and Per2mRNA Levels and Induces Circadian Gene Expression in Cultured Rat-1 Fibroblasts* 210 , 2002, The Journal of Biological Chemistry.

[49]  Steven A. Brown,et al.  Rhythms of Mammalian Body Temperature Can Sustain Peripheral Circadian Clocks , 2002, Current Biology.

[50]  B. H. Miller,et al.  Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock , 2002, Cell.

[51]  Sumio Sugano,et al.  A transcription factor response element for gene expression during circadian night , 2002, Nature.

[52]  Ueli Schibler,et al.  The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator , 2002, Cell.

[53]  Steven M. Reppert,et al.  Rhythmic histone acetylation underlies transcription in the mammalian circadian clock , 2003, Nature.

[54]  M. Nowrousian,et al.  The frequency gene is required for temperature-dependent regulation of many clock-controlled genes in Neurospora crassa. , 2003, Genetics.