The organization of biological activities into daily cycles is universal in organisms as diverse as cyanobacteria, fungi, algae, plants, flies, birds and man. Comparisons of circadian clocks in unicellular and multicellular organisms using molecular genetics and genomics have provided new insights into the mechanisms and complexity of clock systems. Whereas unicellular organisms require stand-alone clocks that can generate 24-hour rhythms for diverse processes, organisms with differentiated tissues can partition clock function to generate and coordinate different rhythms. In both cases, the temporal coordination of a multi-oscillator system is essential for producing robust circadian rhythms of gene expression and biological activity.

http://www.ifc.unam.mx/curso_ritmos/capitulo8/Bell-Pedersen05.pdf

Circadian rhythms from multiple oscillators: lessons from diverse organisms

Suprachiasmatic nucleus: the mind's clock

Recent years have witnessed an explosion of different genomic approaches which, through a combination of advanced biological, instrumental and bioinformatic techniques, can yield a previously unparalleled amount of data concerning the molecular and biochemical status of organisms. Fueled partially by large, well-publicized efforts such as the human genome project, genomic research has become a rapidly growing topical area in multiple biological disciplines. Since 1999 when the term toxicogenomics was coined to describe the application of genomics to toxicology, a citation analysis reveals a rapid increase in publications dealing with the topic. The potential utility of toxicogenomics in toxicological research and regulatory activities has been the subject of scientific discussions and, as with any new technology, there is a wide range of opinion. The purpose of this feature article is to consider roles of toxicogenomics in the field of regulatory ecotoxicology, explore current limitations in the science and practice of genomics, and propose possible avenues to approach and resolve some of the major challenges. A significant amount of input to our analysis came from a workshop sponsored by the Society of Environmental Toxicology and Chemistry in Pellston, MI in September, 2005.

/pdf/toxicogenomics-in-regulatory-ecotoxicology-4v5rkn1w3w.pdf

Toxicogenomics in regulatory ecotoxicology.

Control mechanism of the circadian clock for timing of cell division in vivo

Systems biology is a natural extension of molecular biology; it can be defined as biology after identification of key gene(s). Systems-biological research is a multistage process beginning with (a) the comprehensive identification and (b) quantitative analysis of individual system components and their networked interactions, which lead to the ability to (c) control existing systems toward the desired state and (d) design new ones based on an understanding of the underlying structure and dynamical principles. In this review, we use the mammalian circadian clock as a model system and describe the application of systems-biological approaches to fundamental problems in this model. This application has allowed the identification of transcriptional/posttranscriptional circuits, the discovery of a temperature-insensitive period-determining process, and the discovery of desynchronization of individual clock cells underlying the singularity behavior of mammalian clocks.

/pdf/systems-biology-of-mammalian-circadian-clocks-357kbt1ysz.pdf

Systems Biology of Mammalian Circadian Clocks

Endogenous oscillations in gene expression are a prevalent feature of the circadian clock in the mammalian suprachiasmatic nucleus (SCN) and similar timekeeping systems in other organisms. To determine whether immortalized cells derived from the rat SCN (SCN2.2) retain these intrinsic rhythm-generating properties, oscillatory behavior of the SCN2.2 transcriptome was analyzed and compared with that found in the rat SCN in vivo using rat U34A Affymetrix GeneChips. In SCN2.2 cells, 116 unique genes and 46 ESTs or genes of unknown function exhibited circadian fluctuations with a 1.5-fold or greater difference in their mRNA abundance for two cycles. Many (35%) of these rhythmically regulated genes in SCN2.2 cells also exhibited circadian profiles of mRNA expression in the rat SCN in vivo. Functional analyses and cartography indicate that a diverse set of cellular pathways are strategically regulated by the circadian clock in SCN2.2 cells and that the largest categories of rhythmic genes are those involved in cellular and systems-level communication or in metabolic processes like cellular respiration, fatty acid recycling, and steroid synthesis. Because many of the same genes or nodes within these functional categories were rhythmically expressed in both SCN2.2 cells and the rat SCN, the circadian regulation of these pathways may be important in modulating input to or output from the SCN clock mechanism. In summary, global expression and circadian regulation of the SCN2.2 transcriptome retain many SCN-like properties, suggesting that genes displaying rhythmic profiles in both experimental models may be integral to their function as both circadian oscillators and pacemakers.

https://www.physiology.org/doi/pdf/10.1152/physiolgenomics.00224.2004

Circadian profiling of the transcriptome in immortalized rat SCN cells.

Identification of genes differentially expressed in vascular smooth muscle cells following benzo[a]pyrene challenge: implications for chemical atherogenesis.

Redox regulation of a novel L1Md-A2 retrotransposon in vascular smooth muscle cells.

Atherogenic stimuli trigger complex responses in vascular smooth muscle cells (VSMCs) that culminate in activation/repression of overlapping signal transduction cascades involving oxidative stress. In the case of benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon present in tobacco smoke, the atherogenic response involves interference with redox homeostasis by oxidative intermediates of BaP metabolism. The present studies were conducted to define genomic profiles and predictive gene biological networks associated with the atherogenic response of murine (aortic) VSMCs to BaP. A combined oxidant-antioxidant treatment regimen was used to identify redox-sensitive targets during the early course of the atherogenic response. Gene expression profiles were defined using cDNA microarrays coupled to analysis of variance and several clustering methodologies. A predictor algorithm was then applied to gain insight into critical gene-gene interactions during atherogenesis. Supervised and nonsupervised analyses identified clones highly regulated by BaP, unaffected by antioxidant, and neutralized by combined chemical treatments. Lymphocyte antigen-6 complex, histocompatibility class I component factors, secreted phosphoprotein, and several interferon-inducible proteins were identified as novel redox-regulated targets of BaP. Predictor analysis confirmed these relationships and identified immune-related genes as critical molecular targets of BaP. Redox-dependent patterns of gene deregulation indicate that oxidative stress plays a prominent role during the early stages of BaP-induced atherogenesis.

K. P. Lu

Papers

Circadian profiling of the transcriptome in immortalized rat SCN cells.

Identification of genes differentially expressed in vascular smooth muscle cells following benzo[a]pyrene challenge: implications for chemical atherogenesis.

Redox regulation of a novel L1Md-A2 retrotransposon in vascular smooth muscle cells.

Genomic profiles and predictive biological networks in oxidant-induced atherogenesis.

Novel genomic targets in oxidant-induced vascular injury.