title: Hepatocyte nuclear factor 4α regulates expression of the mouse female-specific Cyp3a41 gene in the liver.
abstract: CYP3A41 is a female-specific cytochrome P450 in mouse liver. A putative hepatocyte nuclear factor 4α (HNF4α)-binding site was found at -99/-87 in the promoter of Cyp3a41 by reporter assays performed in the hepatocytes of female mice. Cotransfection of an HNF4α expression plasmid significantly increased transcription of the reporter gene. Although electrophoretic mobility shift assays with liver nuclear extracts did not show a sex-related difference, chromatin immunoprecipitation (ChIP) assays showed that larger amounts of HNF4α bound to Cyp3a41 in female than in male mice. A relation between the amount of HNF4α on the Cyp3a41 gene and mRNA expression was observed in hepatic tissue sets, which differ in mRNA expression depending on the sex, age, or endocrine status of mice. The degree of histone-3-lysine-4 dimethylation and histone-3-lysine-27 trimethylation around the HNF4α-binding site was higher in females and males, respectively. Moreover, the ChIP assay indicated greater acetylation of histone-4-lysine-8 of the Cyp3a41 chromatin in females than in males. HNF4α plays an important role in the transcriptional activation of the Cyp3a41 gene, and a sex difference in chromatin structure may contribute to the female-specific expression of Cyp3a41 in the livers of mice.
authors.affiliation: Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Wattanaporn
authors.initials: W
authors.lastname: Bhadhprasit
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sakuma
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nemoto
mesh_terms: D000107:Acetylation; D000375:Aging; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D019382:Human Growth Hormone / Q000494:pharmacology; D007016:Hypophysectomy; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012727:Sex Characteristics
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; C496593:Hnf4a protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D003577:Cytochrome P-450 Enzyme System; C408695:Cyp3a41a protein, mouse