Sources of variance in baseline gene expression in the rodent liver

Abstract

The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in liver gene expression in the rodent. Here, studies which highlight contributions of different factors to gene expression variability in the rodent liver are discussed including a large meta-analysis of rat liver, which identified genes that vary in control animals in the absence of chemical treatment. Genes and their pathways that are the most and least variable were identified in a number of these studies. Life stage, fasting, sex, diet, circadian rhythm and liver lobe source can profoundly influence gene expression in the liver. Recognition of biological and technical factors that contribute to variability of background gene expression can help the investigator in the design of an experiment that maximizes sensitivity and reduces the influence of confounders that may lead to misinterpretation of genomic changes. The factors that contribute to variability in liver gene expression in rodents are likely analogous to those contributing to human interindividual variability in drug response and chemical toxicity. Identification of batteries of genes that are altered in a variety of background conditions could be used to predict responses to drugs and chemicals in appropriate models of the human liver.

Sex Differences in the Circadian Variation of Cytochrome P450 Genes and Corresponding Nuclear Receptors in Mouse Liver

“…Sex differences in Cyp expression are most striking in rodents, but are also seen, albeit to a much smaller degree, in humans. Females have a higher incidence of drug-induced liver toxicity (Maddrey, 2005), and this could be due, at least in part, to pharmacokinetic differences in the expression of Cyp genes (Corton et al, 2012). …”

“…Sex differences and circadian variation are two major sources of baseline gene expression variance in rodent livers that affect xenobiotic metabolism and toxicity (Corton et al, 2012). The biological clock in the liver is under the control of the master clock, the suprachiasmatic nucleus located in the brain, and controls Cyp expression to adapt to daily changes that the anticipates sleep and activity periods (Duez et al, 2008; Froy, 2009, 2011; Lim et al, 2006; Paschos et al, 2010).…”

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

“…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).…”

“…Further, the liver is a key regulator of sexually dimorphic immune function: male mice are more susceptible to liver infection than females (Diodato et al, 2001), and these differences are androgen-mediated (Mock and Nacy, 1988) through gene expression changes (Delić et al, 2010). Sex differences in gene expression in liver can be substantial (Corton et al, 2012), and are largely driven by activational effects of hormones (van Nas et al, 2009). The physiological demands of flight are thought to have resulted in a larger liver in birds compared with mammals (Proctor, 1993), making hormonal influences of this organ particularly important in birds.…”

De Novo Transcriptome Assembly and Annotation of Liver and Brain Tissues of Common Brushtail Possums (Trichosurus vulpecula) in New Zealand: Transcriptome Diversity after Decades of Population Control

“…Approximately 1 mm 3 tissue from liver and brain cerebral cortex were excised, transferred to 10:1 volume of RNAlater solution (Qiagen-Hilden) and stored at −80 • C until RNA was extracted within one week after specimen collection. Liver cells are assumed to be more homogeneous in their gene expression profiles, but see Reference [38], whereas brain cell expression profiles often differ considerably between different brain regions [39,40]. To account for variations in the gene expression profiles in the possums' cerebral cortex, brain biopsies from three individuals were excised from different sections of the proximal cerebral cortex in the left and right cortical lobes.…”