Circadian transcription of the cholesterol 7 alpha hydroxylase gene may involve the liver-enriched bZIP protein DBP.
The liver-enriched transcription factor DBP is expressed with a stringent circadian rhythm. We present evidence that DBP is a regulator of the circadian expression of the rat gene encoding cholesterol 7 alpha hydroxylase (C7 alpha H), the rate-limiting enzyme in the conversion of cholesterol to bile acids. As with DBP, C7 alpha H mRNA reaches peak levels in the evening, and its cycling is independent of daily food and light cues. As predicted for a DBP target gene, the primary level of C7 alpha H circadian expression is at the transcriptional level. DBP can activate the C7 alpha H promoter in cotransfection assays through a cognate DNA site centered around -225. In nuclear extracts prepared by a novel method that, in contrast to conventional techniques, yields near-quantitative recovery of DBP and other non-histone proteins, the DNA site required for DBP activation is the predominant site of occupancy by nuclear factors on the C7 alpha H promoter. At this site, the predominant binding activity is an evening-specific complex of which DBP is a component. These data suggest that DBP may play an important role in cholesterol homeostasis through circadian transcriptional regulation of cholesterol 7 alpha hydroxylase.
Lavery
D J
DJ
Département de Biologie Moléculaire, Sciences II, Université de Genève, Switzerland.
Schibler
U
U
D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006706:Homeostasis / Q000235:genetics; D016350:Leucine Zippers; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
C485975:DBP protein, rat; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D002790:Cholesterol 7-alpha-Hydroxylase