Rhythmic expression of DEC1 and DEC2 in peripheral tissues: DEC2 is a potent suppressor for hepatic cytochrome P450s opposing DBP.
The mammalian master molecular clock consisting of several clock gene products in the suprachiasmatic nucleus (SCN) drives circadian rhythms in behaviour and physiology. Molecular clocks consisting of the same components also exist in various peripheral organs. DEC1 and DEC2, basic helix-loop-helix transcription factors, were recently reported to be involved in the central clock in the SCN. We examined the expression profile of DEC1 and DEC2 in the periphery and their roles in the regulation of oscillating target genes in the liver. Levels of DEC1 and DEC2 mRNA exhibited a day-night variation in various peripheral tissues of rats. In the liver, their expression was high during the subjective night. Transfection assays showed that DEC2, but not DEC1, suppressed the transcription of the cholesterol 7alpha-hydroxylase gene (CYP7A), overwhelming the potent enhancement by D-site binding protein (DBP). Electrophoretic mobility shift assays indicated that DEC2 binds to the E-box (CACATG) at the -219/-214 region of CYP7A. The transcriptional activities of the other sterol metabolizing cytochrome P450s (Cyps), CYP8B and CYP51, were also suppressed by DEC2 but not DEC1. DEC2, but not DEC1, works as a direct output mediator that transmits the circadian signals to the hepatic functions, including the CYP7A, CYP8B, and CYP51 expression.
Noshiro
Mitsuhide
M
Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan. noshiro@hiroshima-u.ac.jp
Kawamoto
Takeshi
T
Furukawa
Masae
M
Fujimoto
Katsumi
K
Yoshida
Yuzo
Y
Sasabe
Eri
E
Tsutsumi
Shinichi
S
Hamada
Taizo
T
Honma
Sato
S
Honma
Ken-ichi
K
Kato
Yukio
Y
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013253:Steroid 12-alpha-Hydroxylase / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D002790:Cholesterol 7-alpha-Hydroxylase; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D013253:Steroid 12-alpha-Hydroxylase; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C422085:BHLHE41 protein, human; C485975:DBP protein, rat; C403671:DELEC1 protein, human