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Sexually dimorphic genome-wide binding of retinoid X receptor alpha (RXR?) determines male-female differences in the expression of hepatic lipid processing genes in mice.

ABSTRACT: Many hepatic functions including lipid metabolism, drug metabolism, and inflammatory responses are regulated in a sex-specific manner due to distinct patterns of hepatic gene expression between males and females. Regulation for the majority of these genes is under control of Nuclear Receptors (NRs). Retinoid X Receptor alpha (RXR?) is an obligate partner for multiple NRs and considered a master regulator of hepatic gene expression, yet the full extent of RXR? chromatin binding in male and female livers is unclear. ChIP-Seq analysis of RXR? and RNA Polymerase2 (Pol2) binding was performed livers of both genders and combined with microarray analysis. Mice were gavage-fed with the RXR ligand LG268 for 5 days (30 mg/kg/day) and RXR?-binding and RNA levels were determined by ChIP-qPCR and qPCR, respectively. ChIP-Seq revealed 47,845 (male) and 46,877 (female) RXR? binding sites (BS), associated with ?12,700 unique genes in livers of both genders, with 91% shared between sexes. RXR?-binding showed significant enrichment for 2227 and 1498 unique genes in male and female livers, respectively. Correlating RXR? binding strength with Pol2-binding revealed 44 genes being male-dominant and 43 female-dominant, many previously unknown to be sexually-dimorphic. Surprisingly, genes fundamental to lipid metabolism, including Scd1, Fasn, Elovl6, and Pnpla3-implicated in Fatty Liver Disease pathogenesis, were predominant in females. RXR? activation using LG268 confirmed RXR?-binding was 2-3 fold increased in female livers at multiple newly identified RXR? BS including for Pnpla3 and Elovl6, with corresponding ?10-fold and ?2-fold increases in Pnpla3 and Elovl6 RNA respectively in LG268-treated female livers, supporting a role for RXR? regulation of sexually-dimorphic responses for these genes. RXR? appears to be one of the most widely distributed transcriptional regulators in mouse liver and is engaged in determining sexually-dimorphic expression of key lipid-processing genes, suggesting novel gender- and gene-specific responses to NR-based treatments for lipid-related liver diseases.

SUBMITTER: Kosters A

PROVIDER: S-EPMC3747242 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Sexually dimorphic genome-wide binding of retinoid X receptor alpha (RXRα) determines male-female differences in the expression of hepatic lipid processing genes in mice.

Kosters Astrid A Sun Deqiang D Wu Hao H Tian Feng F Felix Julio C JC Li Wei W Karpen Saul J SJ

PloS one 20130819 8

Many hepatic functions including lipid metabolism, drug metabolism, and inflammatory responses are regulated in a sex-specific manner due to distinct patterns of hepatic gene expression between males and females. Regulation for the majority of these genes is under control of Nuclear Receptors (NRs). Retinoid X Receptor alpha (RXRα) is an obligate partner for multiple NRs and considered a master regulator of hepatic gene expression, yet the full extent of RXRα chromatin binding in male and female ...[more]

PMID: 23977068

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Project description:BackgroundIn most animal groups, it is unclear how body size variation relates to genital size differences between the sexes. While most morphological features tend to scale with total somatic size, this does not necessarily hold for genitalia because divergent evolution in somatic size between the sexes would cause genital size mismatches. Theory predicts that the interplay of female-biased sexual size dimorphism (SSD) and sexual genital size dimorphism (SGD) should adhere to the 'positive genital divergence', the 'constant genital divergence', or the 'negative genital divergence' model, but these models remain largely untested. We test their validity in the spider family Nephilidae known for the highest degrees of SSD among terrestrial animals.ResultsThrough comparative analyses of sex-specific somatic and genital sizes, we first demonstrate that 99 of the 351 pairs of traits are phylogenetically correlated. Through factor analyses we then group these traits for MCMCglmm analyses that test broader correlation patterns, and these reveal significant correlations in 10 out of the 36 pairwise comparisons. Both types of analyses agree that female somatic and internal genital sizes evolve independently. While sizes of non-intromittent male genital parts coevolve with male body size, the size of the intromittent male genital parts is independent of the male somatic size. Instead, male intromittent genital size coevolves with female (external and, in part, internal) genital size. All analyses also agree that SGD and SSD evolve independently.ConclusionsInternal dimensions of female genitalia evolve independently of female body size in nephilid spiders, and similarly, male intromittent genital size evolves independently of the male body size. The size of the male intromittent organ (the embolus) and the sizes of female internal and external genital components thus seem to respond to selection against genital size mismatches. In accord with these interpretations, we reject the validity of the existing theoretical models of genital and somatic size dimorphism in spiders.

Dataset Information

Sexually dimorphic genome-wide binding of retinoid X receptor alpha (RXR?) determines male-female differences in the expression of hepatic lipid processing genes in mice.

Publications

Sexually dimorphic genome-wide binding of retinoid X receptor alpha (RXRα) determines male-female differences in the expression of hepatic lipid processing genes in mice.

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