Genome-wide Expression Analysis of Mouse Liver Reveals CLOCK-regulated Circadian Output Genes

Katsutaka Oishi, Koyomi Miyazaki, Koji Kadota, Reiko Kikuno, Takahiro Nagase, Gen Ichi Atsumi, Naoki Ohkura, Takashi Azama, Miho Mesaki, Shima Yukimasa, Hisato Kobayashi, Chisato Iitaka, Takashi Umehara, Masami Horikoshi, Takashi Kudo, Yoshihisa Shimizu, Masahiko Yano, Morito Monden, Kazuhiko Machida, Juzo MatsudaShuichi Horie, Takeshi Todo, Norio Ishida

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277 Citations (Scopus)

Abstract

CLOCK is a positive component of a transcription/ translation-based negative feedback loop of the central circadian oscillator in the suprachiasmatic nucleus in mammals. To examine CLOCK-regulated circadian transcription in peripheral tissues, we performed microarray analyses using liver RNA isolated from Clock mutant mice. We also compared expression profiles with those of Cryptochromes (Cry1 and Cry2) double knockout mice. We identified more than 100 genes that fluctuated from day to night and of which expression levels were decreased in Clock mutant mice. In Cry-deficient mice, the expression levels of most CLOCK-regulated genes were elevated to the upper range of normal oscillation. Most of the screened genes had a CLOCK/BMAL1 binding site (E box) in the 5′-flanking region. We found that CLOCK was absolutely concerned with the circadian transcription of one type of liver genes (such as DBP, TEF, and Usp2) and partially with another (such as mPer1, mPer2, mDec1, Nocturnin, P450 oxidoreductase, and FKBP51) because the latter were damped but remained rhythmic in the mutant mice. Our results showed that CLOCK and CRY proteins are involved in the transcriptional regulation of many circadian output genes in the mouse liver. In addition to being a core component of the negative feedback loop that drives the circadian oscillator, CLOCK also appears to be involved in various physiological functions such as cell cycle, lipid metabolism, immune functions, and proteolysis in peripheral tissues.

Original languageEnglish
Pages (from-to)41519-41527
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number42
DOIs
Publication statusPublished - 2003 Oct 17

ASJC Scopus subject areas

  • Biochemistry

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    Oishi, K., Miyazaki, K., Kadota, K., Kikuno, R., Nagase, T., Atsumi, G. I., Ohkura, N., Azama, T., Mesaki, M., Yukimasa, S., Kobayashi, H., Iitaka, C., Umehara, T., Horikoshi, M., Kudo, T., Shimizu, Y., Yano, M., Monden, M., Machida, K., ... Ishida, N. (2003). Genome-wide Expression Analysis of Mouse Liver Reveals CLOCK-regulated Circadian Output Genes. Journal of Biological Chemistry, 278(42), 41519-41527. https://doi.org/10.1074/jbc.M304564200