Elucidating the Role of Gonadal Hormones in Sexually Dimorphic Gene Coexpression Networks

Abstract

We previously used high-density expression arrays to interrogate a genetic cross between strains C3H/HeJ and C57BL/6J and observed thousands of differences in gene expression between sexes. We now report analyses of the molecular basis of these sex differences and of the effects of sex on gene expression networks. We analyzed liver gene expression of hormone-treated gonadectomized mice as well as XX male and XY female mice. Differences in gene expression resulted in large part from acute effects of gonadal hormones acting in adulthood, and the effects of sex chromosomes, apart from hormones, were modest. We also determined whether there are sex differences in the organization of gene expression networks in adipose, liver, skeletal muscle, and brain tissue. Although coexpression networks of highly correlated genes were largely conserved between sexes, some exhibited striking sex dependence. We observed strong body fat and lipid correlations with sex-specific modules in adipose and liver as well as a sexually dimorphic network enriched for genes affected by gonadal hormones. Finally, our analyses identified chromosomal loci regulating sexually dimorphic networks. This study indicates that gonadal hormones play a strong role in sex differences in gene expression. In addition, it results in the identification of sex-specific gene coexpression networks related to genetic and metabolic traits.

Female competition and aggression: interdisciplinary perspectives

“…The affected genes included those known to mediate aggression, notably aromatase and monoamine oxidase A [123]. Importantly, males and females overlapped in less than 1% of genes affected by T treatment, suggestive of sex-specific genomic responses to T. There is also intriguing evidence that gene networks (genes whose expression are correlated) are more modular in females and this may allow females to regulate parcels of genes in a modular fashion [124]. Hence this may allow females greater flexibility to express aggressive behaviour while still maintaining normal fertility and parental behaviour [121].…”

Biochip analysis of prostate cancer

“…Weighted gene co-expression network analyses are increasingly used to explore the system-level functionality of genes whose construction is conceptually straightforward: nodes represent genes, and nodes are connected if the corresponding genes are significantly co-expressed across appropriately chosen tissue samples (Mason et al, 2009;Van Nas et al, 2009). Furthermore, the association of a specific gene's expression, such as platelet-derived growth factor receptor (PDGFR), with its outcome raises the possibility that expression analysis may prove useful in selecting patients for emerging mechanism-based therapeutics.…”

“…Recently, genomic methodologies have been used to discover consistent gene expression patterns associated with a given histological or clinical phenotype (Golub et al, 1999;Perou et al, 2000;Van't Veer et al, 2002). Here, gene expression patterns of tissues from normal prostate, primary prostate cancer, and metastatic prostate cancer were studied in order to analyze changes in biochemical pathways possibly leading to primary and metastatic prostate cancer.…”

Le dimorphisme sexuel au XXIesiècle

“…Dans le tissu adipeux, le cerveau, le foie et le muscle, ce dimorphisme sexuel est détecté à l'échelle de modules de réseaux régulés par ces loci chromosomiques et par les hormones gonadiques. Ces réseaux spécifiques du sexe sont fortement corrélés à des traits génétiques et métaboliques [25]. C'est le cas pour les gènes spécifiquement mâles comme Cyp2a2, ou femelles comme Cyp2c12, codant pour des cytochromes P450 (voir ci-dessous) [25].…”

“…Ces réseaux spécifiques du sexe sont fortement corrélés à des traits génétiques et métaboliques [25]. C'est le cas pour les gènes spécifiquement mâles comme Cyp2a2, ou femelles comme Cyp2c12, codant pour des cytochromes P450 (voir ci-dessous) [25]. Dans une autre étude portant sur le foie adulte, on a pu estimer que la part du rôle des gènes localisés sur les chromosomes sexuels dans la modulation de l'expression spécifique du sexe semble modeste (10 %), par rapport au rôle dominant des hormones sexuelles [26].…”