title: Sex-dependent regulation of cytochrome P450 family members Cyp1a1, Cyp2e1, and Cyp7b1 by methylation of DNA.
abstract: Sexual differences are only partially attributable to hormones. Cultured male or female cells, even from embryos before sexual differentiation, differ in gene expression and sensitivity to toxins, and these differences persist in isolated primary cells. Male and female cells from Swiss Webster CWF mice manifest sex-distinct patterns of DNA methylation for X-ist and for cytochrome P450 (CYP; family members 1a1, 2e1m, and 7b1. Dnmt3l is differentially expressed but not differentially methylated, and Gapdh is neither differentially methylated nor expressed. CYP family genes differ in expression in whole tissue homogenates and cell cultures, with female Cyp expression 2- to 355-fold higher and Dnmt3l 12- to 32-fold higher in males. DNA methylation in the promoters of these genes is sex dimorphic; reducing methylation differences reduces to 1- to 6-fold differences in the expression of these genes. Stress or estradiol alters both methylation and gene expression. We conclude that different methylation patterns partially explain the sex-based differences in expression of CYP family members and X-ist, which potentially leads to inborn differences between males and females and their different responses to chronic and acute changes. Sex-differential methylation may have medical effects.
authors.affiliation: 1Queens College, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY 11367, USA. zahra_zakeri@hotmail.com.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Penaloza
authors.forename: Brian
authors.initials: B
authors.lastname: Estevez
authors.forename: Dinah M
authors.initials: DM
authors.lastname: Han
authors.forename: Melissa
authors.initials: M
authors.lastname: Norouzi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lockshin
authors.forename: Zahra
authors.initials: Z
authors.lastname: Zakeri
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D000072474:Cytochrome P450 Family 7; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D000077209:Decitabine; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics*; D013447:Sulfites / Q000494:pharmacology
chemical_list: D013447:Sulfites; D004958:Estradiol; D000077209:Decitabine; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human; C412484:DNMT3L protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine; C009279:sodium bisulfite
keywords: 17β-estradiol; 5-aza-2′-deoxycytidine; X-ist; estrogen; gender; sexual dimorphism; sodium bisulfite