Sex-specific gene expression in the BXD mouse liver

Abstract

Differences in clinical phenotypes between the sexes are well documented and have their roots in differential gene expression. While sex has a major effect on gene expression, transcription is also influenced by complex interactions between individual genetic variation and environmental stimuli. In this study, we sought to understand how genetic variation affects sex-related differences in liver gene expression by performing genetic mapping of genomewide liver mRNA expression data in a genetically defined population of naive male and female mice from C57BL/6J, DBA/2J, B6D2F1, and 37 C57BL/6J × DBA/2J (BXD) recombinant inbred strains. As expected, we found that many genes important to xenobiotic metabolism and other important pathways exhibit sexually dimorphic expression. We also performed gene expression quantitative trait locus mapping in this panel and report that the most significant loci that appear to regulate a larger number of genes than expected by chance are largely sex independent. Importantly, we found that the degree of correlation within gene expression networks differs substantially between the sexes. Finally, we compare our results to a recently released human liver gene expression data set and report on important similarities in sexually dimorphic liver gene expression between mouse and human. This study enhances our understanding of sex differences at the genome level and between species, as well as increasing our knowledge of the molecular underpinnings of sex differences in responses to xenobiotics.

Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids

“…search for clues on the role of Ehhadh, we generated gene coexpression subnetworks using published liver microarray data. We selected three independent mouse experiments: an F 2 intercross between C57BL/6 and BTBR mouse strains in which all cases are homozygous for the obese mutation in the leptin gene (the B6BTBRF2 cross [ 25 ]), an intercross between C57BL/6 and DBA/2J (the BxD genetic reference population [ 26,27 ]), and an F 2 intercross with C57BL/6J x C3H/ HeJ on an ApoE null background (BHF2 [ 28 ]). These experiments make use of genetic variation between four inbred strains (C57BL/6, BTBR, DBA, and C3H) and thereby enable the study of the effect of this genetic variation on mutant backgrounds known to greatly infl uence metabolism (ApoE null and ob/ob backgrounds).…”

“…We selected liver microarray data from three independently generated panels of genetically heterogeneous mice, an F 2 intercross between C57BL/6 and BTBR mouse strains in which all cases are homozygous for the obese mutation in the leptin gene (the B6BTBRF2 cross; n = 41) ( 25 ), an intercross between C57BL/6 and DBA/2J (the BxD genetic reference population; n = 60 male mice) ( 26,27 ), and an F 2 intercross with C57BL/6J x C3H/HeJ on an ApoE null background (BHF2) ( 28 ). We used the (B6 x BTBR)F2-ob/ob Liver mRNA M430 RMA, UNC Agilent G4121A Liver Orig LOWESS Stanford (male mice), and UCLA BHF2 Liver Male mlratio datasets, respectively.…”

Potential for sexual conflict assessed via testosterone-mediated transcriptional changes in liver and muscle of a songbird

“…For example, hydroxysteroid dehydrogenase like 2 (HSDL2) was expressed more highly in the liver of control males than females. HSDL2 plays a role in sterol binding (Dai et al, 2003), and is marginally more highly expressed in the liver of females than males in mice (Gatti et al, 2010). This suggests that the sexes might differ in their metabolism of sterol-based compounds in the liver, but that this difference may vary between taxa.…”

“…Sexually dimorphic patterns of gene expression are thought to account for many of the physiological differences between the sexes (Xu et al, 2012). For example, sex differences in liver gene expression are substantial in rodents (Corton et al, 2012), and explain several known sex differences in liver metabolism (Gatti et al, 2010).…”

Visualization of Sex-Dimorphic Changes in the Intestinal Transcriptome of <b><i>Fabp2</i></b> Gene-Ablated Mice

“…This is especially true of the organs responsible for the acquisition, trafficking, and metabolism of nutrients and xenobiotics such as the intestine and liver. Sex differences in the abundance of master regulators of lipid/energy (PPAR signaling pathway) [2,3,4] and xenobiotic (CYP450 superfamily) [5,6,7,8] metabolism are well documented. Consequently, numerous studies have documented sex differences in the response to fibrates, synthetic PPARα agonists designed to normalize blood lipids and reduce metabolic disease risk [9,10,11,12].…”