Promoter Analysis of Mammalian Clock Controlled Genes

Katarzyna Bożek[1] (k.bozek@biologie.hu-berlin.de)
Szymon M. Kiełbasa[2] (kielbasa@molgen.mpg.de)
Achim Kramer[3] (achim.kramer@charite.de)
Hanspeter Herzel[1] (h.herzel@biologie.hu-berlin.de)

[1]Institute for Theoretical Biology, Humboldt University, Invalidenstraße 43, D-10115 Berlin, Germany
[2]Max Planck Institute for Molecular Genetics, Ihnestrasse 63.73, 14195 Berlin, Germany
[3]Laboratory of Chronobiology, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Hessische Str. 3.4, 10115 Berlin, Germany


Abstract

The circadian clock is a biological system providing an internal self-sustained temporal framework and adaptation mechanisms to the daily environmental rhythm. One of its behavioral implication in humans is the sleep-wake cycle. The core mammalian circadian clock is a system composed of interacting regulatory feedback loops present in many tissues throughout the body. The core set of circadian clock genes codes for proteins feeding back to regulate not only their own expression, but also that of clock output genes and regulatory pathways. Still, however, our understanding of processes regulated in a circadian fashion and the linkage between the molecular system and behavioral or physiological outputs is poor. Our work aims at identification of clock-controlled genes (CCGs) and their regulatory motifs. We analyzed several microarray measurements of genes with a daily oscillating expression and extracted 2065 of them together with their peak expression phases and oscillation amplitudes. For an in-depth analysis we selected a subset of 167 genes reported by multiple microarray experiments. Gene promoters were scanned in the search for known regulatory motifs of clock genes (E-Box, RRE, D-Box, CRE) as well as other over-represented regulatory motifs. We found an overrepresentation of the E-boxes and D-boxes in the selected subset of 167 CCGs. This over-representation is smaller when the list of 2065 genes is analyzed. The search for other regulatory motifs contained in the TRANSFAC database revealed a strong overrepresentation of some of them such as Sp1, AP-2, STAT1, HIF-1 and E2F. The signals found in the promoter sequences indicate possible regulatory mechanisms important for the coordination of circadian rhythms.

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Japanese Society for Bioinformatics