Abstract
The liver is one of the most sex-dimorphic organs in both oviparous and viviparous animals. In order to understand the molecular basis of the difference between male and female livers, high-throughput RNA-SAGE (serial analysis of gene expression) sequencing was performed for zebrafish livers of both sexes and their transcriptomes were compared. Both sexes had abundantly expressed genes involved in translation, coagulation and lipid metabolism, consistent with the general function of the liver. For sex-biased transcripts, from in addition to the high enrichment of vitellogenin transcripts in spawning female livers, which constituted nearly 80% of total mRNA, it is apparent that the female-biased genes were mostly involved in ribosome/translation, estrogen pathway, lipid transport, etc, while the male-biased genes were enriched for oxidation reduction, carbohydrate metabolism, coagulation, protein transport and localization, etc. Sexual dimorphism on xenobiotic metabolism and anti-oxidation was also noted and it is likely that retinol x receptor (RXR) and liver x receptor (LXR) play central roles in regulating the sexual differences of lipid and cholesterol metabolisms. Consistent with high ribosomal/translational activities in the female liver, female-biased genes were significantly regulated by two important transcription factors, Myc and Mycn. In contrast, Male livers showed activation of transcription factors Ppargc1b, Hnf4a, and Stat4, which regulate lipid and glucose metabolisms and various cellular activities. The transcriptomic responses to sex hormones, 17β-estradiol (E2) or 11-keto testosterone (KT11), were also investigated in both male and female livers and we found that female livers were relatively insensitive to sex hormone disturbance, while the male livers were readily affected. E2 feminized male liver by up-regulating female-biased transcripts and down-regulating male-biased transcripts. The information obtained in this study provides comprehensive insights into the sexual dimorphism of zebrafish liver transcriptome and will facilitate further development of the zebrafish as a human liver disease model.
Highlights
The liver plays a critical role in the coordination of various physiological processes including digestion, metabolism, detoxification, biosynthesis of serum proteins, endocrine and immune response, etc
One microarray-based study in zebrafish has indicated that female livers have higher levels of transcripts associated with translation, while the male up-regulated genes are associated with oxidative metabolism, carbohydrate metabolism, energy production, and amelioration of oxidative stress [24]
As the female liver devotes a large portion of its energy to vitellogenesis, gene ontology analysis of the female-biased transcripts showed high enrichment of ribosomal proteins to support the active protein synthesis of vitellogenins and other maternal proteins to be deposited to the oocytes (Table S3)
Summary
The liver plays a critical role in the coordination of various physiological processes including digestion, metabolism, detoxification, biosynthesis of serum proteins, endocrine and immune response, etc. Because of the different metabolic needs for male and female reproduction, the liver is one of the most sexually dimorphic organs in terms of gene expression [1]. One microarray-based study in zebrafish has indicated that female livers have higher levels of transcripts associated with translation, while the male up-regulated genes are associated with oxidative metabolism, carbohydrate metabolism, energy production, and amelioration of oxidative stress [24].
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