Rhythmic expression of DEC1 and DEC2 in peripheral tissues: DEC2 is a potent suppressor for hepatic cytochrome P450s opposing DBP

Abstract

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 7α α α α -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 cytochorme 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.

BHLHB3: a candidate tumor suppressor in lung cancer

“…BHLHB3 has been reported to suppress transcription of the CYP7A gene in a hepatocarcinoma cell line (Noshiro et al, 2004). Consistent with that study, Figure 1 mRNA expression levels in normal and tumor lung tissue of lung adenocarcinoma (ADCA) patients.…”

Bile acids: regulation of synthesis

“…In humans, bile acid synthesis exhibits a diurnal rhythm with two peaks around 3 and 9 PM. CYP7A1 expression is induced by diurnal regulated D-site binding protein (86)(87)(88)(89) and Rev-erb ␣ ( 90 ) but repressed by the clock genes DEC2 and E4BP4 ( 90,91 ). These authors conclude that the circadian rhythm of Cyp7a1 is regulated directly by D-site binding protein, DEC2, and Rev-erb ␣ / ␤ .…”

Expression of the liver‐specific gene Cyp7a1 reveals hepatic differentiation in embryoid bodies derived from mouse embryonic stem cells

“…The mRNA expression of Cyp7a1 is regulated by multiple factors involved in a circadian cycle, bile acid feedback inhibition, and stimulation by oxycholesterol, dexamethasone, and thyroid hormone (Hylemon et al 1992;Davis et al 2002;Noshiro et al 2004). The promoter region located 0.4 kb upstream contains a glucocorticoid response element, binding sites for d-element-binding protein, DEC2, C/EBPα, Foxa2, and HNF-4, and bile acid response elements (Ramirez et al 1994;Davis et al 2002;Noshiro et al 2004). These factors are known to be involved in the liver-specific expression of the Cyp7a1 gene.…”