Abstract
A model-driven discovery process, Computing Life, is used to identify an ensemble of genetic networks that describe the biological clock. A clock mechanism involving the genes white-collar-1 and white-collar-2 (wc-1 and wc-2) that encode a transcriptional activator (as well as a blue-light receptor) and an oscillator frequency (frq) that encodes a cyclin that deactivates the activator is used to guide this discovery process through three cycles of microarray experiments. Central to this discovery process is a new methodology for the rational design of a Maximally Informative Next Experiment (MINE), based on the genetic network ensemble. In each experimentation cycle, the MINE approach is used to select the most informative new experiment in order to mine for clock-controlled genes, the outputs of the clock. As much as 25% of the N. crassa transcriptome appears to be under clock-control. Clock outputs include genes with products in DNA metabolism, ribosome biogenesis in RNA metabolism, cell cycle, protein metabolism, transport, carbon metabolism, isoprenoid (including carotenoid) biosynthesis, development, and varied signaling processes. Genes under the transcription factor complex WCC ( = WC-1/WC-2) control were resolved into four classes, circadian only (612 genes), light-responsive only (396), both circadian and light-responsive (328), and neither circadian nor light-responsive (987). In each of three cycles of microarray experiments data support that wc-1 and wc-2 are auto-regulated by WCC. Among 11,000 N. crassa genes a total of 295 genes, including a large fraction of phosphatases/kinases, appear to be under the immediate control of the FRQ oscillator as validated by 4 independent microarray experiments. Ribosomal RNA processing and assembly rather than its transcription appears to be under clock control, suggesting a new mechanism for the post-transcriptional control of clock-controlled genes.
Highlights
To explain how a complex trait works, systems biology begins with organizing macromolecules into a genetic network [1]
Only sixteen clock-controlled genes have been discovered in N. crassa in over 40 years of clock biology [59]
It is quite remarkable that only three genes, wc-1, wc-2, and frq, could have such diverse and pleiotropic effects on the organism’s transcriptome, and the full extent of the clock’s role in the metabolic web has not been evidenced till
Summary
To explain how a complex trait works, systems biology begins with organizing macromolecules into a genetic network [1]. For two reasons much of what we know about the clock at the molecular level comes from the study of the filamentous fungus, Neurospora crassa [2]. This complex trait is easy to observe and to manipulate in N. crassa (Fig. 1). As a well-studied microbial system, it has been possible to identify three molecular building blocks of the clock, the genes white-collar-1 (wc-1), white-collar-2 (wc-2), and frequency (frq). The genes wc-1 and wc-2 encode PASdomain containing transcription factors [3] that turn on the clock oscillator. The gene frq encodes the clock oscillator FRQ [5] and is activated by the WHITE-COLLAR transcription factor protein complex WCC = WC-1/WC-2. The FRQ protein in turn appears to function as a cyclin to recruit an as yet to be identified kinase/phosphatase pair for the phosphorylation-dependent inactivation of WCC [6]
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