Gender Differences In Gene Expression Research Articles

Integration of segmented regression analysis with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues.

Gene expression alterations occurring with aging have been described for a multitude of species, organs, and cell types. However, most of the underlying studies rely on static comparisons of mean gene expression levels between age groups and do not account for the dynamics of gene expression throughout the lifespan. These studies also tend to disregard the pairwise relationships between gene expression profiles, which may underlie commonly altered pathways and regulatory mechanisms with age. To overcome these limitations, we have combined segmented regression analysis with weighted gene correlation network analysis (WGCNA) to identify high-confidence signatures of aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice in a publicly available RNA-Seq dataset (GSE132040). Functional enrichment analysis of the overlap of genes identified in both approaches showed that immune- and inflammation-related responses are prominently altered in the brain and the liver, while in the heart and the muscle, aging affects amino and fatty acid metabolism, and tissue regeneration, respectively, which reflects an age-related global loss of tissue function. We also explored sexual dimorphism in the aging mouse transcriptome and found the liver and the muscle to have the most pronounced gender differences in gene expression throughout the lifespan, particularly in proteostasis-related pathways. While the data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, which we highlight as important features of murine tissue physiological aging.

The restructuring of dopamine receptor subtype gene transcripts in c-fos KO mice

Although c-Fos protein is one of the principal molecules in intracellular signaling, c-fos gene disruption is associated with alterations in neuronal functions that do not correspond to its importance in function. The aim of the study was to evaluate the changes of dopaminergic system together with acetylcholinesterase (AChE) in c-fos disruption (KO). KO male mice showed an increase in D₁-like receptor (279% of WT) and D₂-like receptor (345% of WT) binding sites in the cortex. On the gene expression level (assessed by real-time PCR), lower quantities of D₁R-mRNA (0.64) and D₅R-mRNA (0.6) were found in females when compared to males in the frontal cortex, higher D₂R-mRNA in the parietal (1.43) and temporal (2.64) cortex and lower AChE-mRNA (0.67). On the contrary, female striatum contained higher level of D₂R-mRNA (1.62) and AChE-mRNA (1.57) but lower level of D₃R-mRNA (0.73). Hypothalamic D₁R-mRNA, D₂R-mRNA and D₄R-mRNA were higher in females (1.38, 1.63, and 1.68, respectively). Disruption of c-fos increased selectively D₅R-mRNA (1.31) in male parietal cortex, D₂R-mRNA (1.72) in male temporal cortex, and cerebellar D₂R-mRNA in both males (1.43) and females (1.42), respectively. In females, we found rather decrease in DR-mRNA. Multiple correlations in mRNA quantities (in WT mice) were found, which changed considerably upon c-fos KO. Main interactions in WT were inter-regional, CNS of KO underwent an extensive restructuring comprising intraregional interactions in the frontal cortex, hypothalamus, and cerebellum. These changes in DR (between others) could be considered as one of the adaptive mechanisms in c-fos KO mice.

Gender segregation in gene expression and vulnerability to oxidative stress induced injury in ventral mesencephalic cultures of dopamine neurons

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNC). Most epidemiologic studies have demonstrated that PD has a higher prevalence in males than in females. Both hormones and genetic factors have been considered to be contributors to this phenomenon. In the present study, we used primary cultures of ventral mesencephalic (VM) neurons from E13.5 Balb/C mice to investigate whether there were any gender differences in gene expression and cell sensitivity to oxidative stress in sex segregated cultures. We also investigated the role of SRY, the sex-determining region on the Y chromosome, and the female hormone estrogen in the gender dimorphism. We measured the expression levels of genes that previously were thought to be related to PD or DA neuron development and functions by real-time PCR, and found six of them, ATP13A2, ERβ, MAO-A, D2, DAT, and Pitx3, showing significantly differential expression between males and females in the normal physiological state or under stress conditions. Furthermore, we demonstrated that male VM neurons are more vulnerable than female neurons to rotenone-induced cytotoxicity and that 17β-estrogen has a moderate protective effect in both male and female VM neurons. Moreover, we document that SRY can upregulate monoamine oxidase A and downregulate estrogen receptor-β, and SRY-overexpressing N2A cells enhance the resistance to oxidative stress-induced cell injury. Our results suggest that gender indeed influences several PD-related gene expressions in VM neurons, and SRY and estrogen are involved in the different responses to oxidative stress in culture.

Transcriptome analysis of male–female differences in prefrontal cortical development

Human neuropsychiatric disorders that involve the prefrontal cortex show gender differences in age of onset, prevalence and symptomatology. Gender dimorphisms in human-brain development may include differential cortical expression of genes on both the sex chromosomes1, 2 and on the autosomes. Here we identify gender differences in gene expression during human cortical development that may illuminate the molecular basis of gender biases in vulnerability to brain disorders.

Basal Gene Expression in Male and Female Sprague-Dawley Rat Nasal Respiratory and Olfactory Epithelium

The nasal epithelium is an important target site for chemically induced toxicity and carcinogenicity. Experimental studies show that site-specific lesions can arise within the nasal respiratory or olfactory epithelium following the inhalation of certain chemicals. Moreover, gender differences in epithelial response are also reported. To better understand and predict gender differences in response of the nasal epithelium to inhaled xenobiotics, gene expression profiles from naive male and female Sprague-Dawley rats were constructed. Epithelial cells were manually collected from the nasal septum, naso- and maxillo-turbinates, and ethmoid turbinates of nine male and nine female rats. Gene expression analysis was performed using the Affymetrix Rat Genome 430 2.0 microarray. Surprisingly, there were few gender differences in gene expression. Gene ontology enrichment analysis identified several functional categories, including xenobiotic metabolism, cell cycle, apoptosis, and ion channel/transport, with significantly different expression between tissue types. These baseline data will contribute to our understanding of the normal physiology and selectivity of the nasal epithelial cells' response to inhaled environmental toxicants.

Nonylphenol modulates expression of androgen receptor and estrogen receptor genes differently in gender types of the hermaphroditic fish Rivulus marmoratus

To uncover the effect of estrogenic chemicals [4-nonylphenol (NP) and bisphenol A (BisA)] on the expression of androgen receptor (AR) and estrogen receptors (ERα and ERβ) in the hermaphroditic fish Rivulus marmoratus, we cloned the full length of the cDNAs encoding AR, ERα, and ERβ from gonadal tissue of R. marmoratus and analyzed the modulation of expression of these genes following exposure to estrogenic chemicals using real-time RT-PCR. R. marmoratus AR, ERα, and ERβ genes showed a high similarity to the relevant fish species on amino acid residues, respectively. Rm-ER α and Rm-ERβ cDNAs included a serine-rich region when compared to other teleost fish ER genes. Tissue-specific expression of Rm-AR and Rm-ERβ mRNAs in adult hermaphrodite R. marmoratus was high in the gonad, while Rm-ERα mRNA was high in the liver based on real-time RT-PCR. In addition, Rm-AR and Rm-ERα mRNAs increased along with developmental stage from stage 3 (5 dpf) to hatching, while Rm-ERβ mRNA increased from stage 2 (2 dpf). To uncover the effect of estrogenic chemicals on R. marmoratus, we exposed the fish to NP (300 μg/l) and BisA (600 μg/l) for 96 h. Significant down-regulation of Rm-AR, Rm-ERα, and Rm-ERβ mRNA was observed in gonadal tissue after exposure to NP but not BisA. In the liver, there were gender differences in gene expression after EDC exposure. These results demonstrate that expression patterns of the Rm-AR, Rm-ERα, and Rm-ERβ genes in the hermaphroditic fish, R. marmoratus, vary according to tissue and developmental stage as well as the specificity of environmental estrogenic chemicals. These genes can be useful as molecular biomarkers in assessing the potential impact of estrogenic compounds using this species as a model system.

Genome-wide estimation of gender differences in the gene expression of human livers: Statistical design and analysis

BackgroundGender differences in gene expression were estimated in liver samples from 9 males and 9 females. The study tested 31,110 genes for a gender difference using a design that adjusted for sources of variation associated with cDNA arrays, normalization, hybridizations and processing conditions.ResultsThe genes were split into 2,800 that were clearly expressed (expressed genes) and 28,310 that had expression levels in the background range (not expressed genes). The distribution of p-values from the 'not expressed' group was consistent with no gender differences. The distribution of p-values from the 'expressed' group suggested that 8 % of these genes differed by gender, but the estimated fold-changes (expression in males / expression in females) were small. The largest observed fold-change was 1.55. The 95 % confidence bounds on the estimated fold-changes were less than 1.4 fold for 79.3 %, and few (1.1%) exceed 2-fold.ConclusionObserved gender differences in gene expression were small. When selecting genes with gender differences based upon their p-values, false discovery rates exceed 80 % for any set of genes, essentially making it impossible to identify any specific genes with a gender difference.

Molecular phenotyping for analyzing subtle genetic effects in mice: application to an angiotensinogen gene titration.

The angiotensinogen M235T polymorphism in humans is linked to differential expression of the human angiotensinogen gene (AGT) gene and hypertension, but the homeostatic responses resulting from this polymorphism are not known. We therefore investigated how mice respond to five genetically determined levels of mouse angiotensinogen gene (Agt) expression covering the range associated with the M235T variants. By using high-throughput molecular phenotyping, tissue RNAs were assayed for expression of 10 genes important in hypertension. Significant positive and negative responses occurred in both sexes as Agt expression increased twofold, including a three-fold increase in aldosterone synthase expression in adrenal gland, and a two-fold decrease in renin expression in kidney. In males, cardiac expression of the precursor of atrial natriuretic peptide B and of adrenomedullin also increased approximately twofold. The relative expression of all genes studied except Agt differed significantly in the two sexes, and several unexpected relationships were encountered. A highly significant correlation between renal expression of the angiotensin type 1a receptor and kallikrein, independent of Agt genotype, is present in females (P < 0.0001) but not males (P = 0.4). The correlation between blood pressure (BP) and liver Agt expression within the five Agt genotypes is significant in females (P = 0.0005) but not in males (P = 0.2), whereas correlation of BP with differences between the genotypes is less in females (P = 0.06) than in males (P = 0.001). The marked gender differences in gene expression in wild-type mice and the changes induced by moderate alterations in Agt expression and BP emphasize the need to look for similar differences in humans.

Gender differences in molecular remodeling in pressure overload hypertrophy

OBJECTIVESThe objective of this study was to examine gender differences in left ventricular (LV) function and expression of cardiac genes in response to LV pressure overload due to ascending aortic stenosis in rats.BACKGROUNDClinical studies have documented gender differences in the pattern of adaptive LV hypertrophy. Whether these differences result from intrinsic differences in molecular adaptation to pressure overload between men and women, or are related to other factors is not known.METHODSMale (n = 8) and female (n = 8) Wistar rats underwent ascending aortic stenosis and were studied 6 weeks after banding with gender-matched control rats (male n = 7; female n = 7). The LV contractile reserve was examined in isolated hearts from each group. We compared LV messenger ribonucleic acid (mRNA) levels of atrial natriuretic factor (ANF), beta-myosin heavy chain, sarcoplasmic reticulum Ca2+–adenosine triphosphatase (ATPase) and Na+–Ca2+exchanger. Reverse transcriptase polymerase chain reaction was used to identify estrogen receptor transcript in cardiac myocytes and LV tissue.RESULTSThe magnitude of LV hypertrophy (LVH) and systolic wall stress were similar in male and female animals with LVH. Male LVH hearts demonstrated a depressed contractile reserve; in contrast, contractile reserve was preserved in female LVH hearts. The expression of beta-myosin heavy chain and ANF mRNA was greater in male versus female LVH hearts. Sarcoplasmic reticulum Ca2+-ATPase mRNA levels were depressed in male LVH but not in female LVH compared with control rats, and Na+–Ca2+exchanger mRNA levels were increased similarly in both male and female LVH hearts. Estrogen receptor transcript was detected in both adult male and female cardiac myocytes and LV tissue.CONCLUSIONSThere are significant gender differences in the LV adaptation to pressure overload despite a similar degree of LVH and systolic wall stress in male and female rats. There is the potential for estrogen signaling through the adult myocyte estrogen receptor in both male and female rats to contribute to gender differences in gene expression in pathologic hypertrophy.