Abstract
BackgroundEarly liver development and the transcriptional transitions during hepatogenesis are well characterized. However, gene expression changes during the late postnatal/pre-pubertal to young adulthood period are less well understood, especially with regards to sex-specific gene expression.MethodsMicroarray analysis of male and female mouse liver was carried out at 3, 4, and 8 wk of age to elucidate developmental changes in gene expression from the late postnatal/pre-pubertal period to young adulthood.ResultsA large number of sex-biased and sex-independent genes showed significant changes during this developmental period. Notably, sex-independent genes involved in cell cycle, chromosome condensation, and DNA replication were down regulated from 3 wk to 8 wk, while genes associated with metal ion binding, ion transport and kinase activity were up regulated. A majority of genes showing sex differential expression in adult liver did not display sex differences prior to puberty, at which time extensive changes in sex-specific gene expression were seen, primarily in males. Thus, in male liver, 76% of male-specific genes were up regulated and 47% of female-specific genes were down regulated from 3 to 8 wk of age, whereas in female liver 67% of sex-specific genes showed no significant change in expression. In both sexes, genes up regulated from 3 to 8 wk were significantly enriched (p < E-76) in the set of genes positively regulated by the liver transcription factor HNF4α, as determined in a liver-specific HNF4α knockout mouse model, while genes down regulated during this developmental period showed significant enrichment (p < E-65) for negative regulation by HNF4α. Significant enrichment of the developmentally regulated genes in the set of genes subject to positive and negative regulation by pituitary hormone was also observed. Five sex-specific transcriptional regulators showed sex-specific expression at 4 wk (male-specific Ihh; female-specific Cdx4, Cux2, Tox, and Trim24) and may contribute to the developmental changes that lead to global acquisition of liver sex-specificity by 8 wk of age.ConclusionsOverall, the observed changes in gene expression during postnatal liver development reflect the deceleration of liver growth and the induction of specialized liver functions, with widespread changes in sex-specific gene expression primarily occurring in male liver.
Highlights
Liver development and the transcriptional transitions during hepatogenesis are well characterized
We show that genes that show changes during this period of development are enriched in the set of genes whose expression is dependent on the liver transcription factor hepatocyte nuclear factor 4a (HNF4a) [24], as determined using a liver-specific mouse HNF4a knockout model [25]
Genes were classified as male-specific (587 genes), female-specific (625 genes), or sex-independent (4,503 genes) based on their expression profiles in male compared to female liver at 8 wk of age (Table 1)
Summary
Liver development and the transcriptional transitions during hepatogenesis are well characterized. Gene expression changes during the late postnatal/pre-pubertal to young adulthood period are less well understood, especially with regards to sex-specific gene expression. Liver development begins around embryonic day 9 (E9) in the mouse and the transcriptional transitions during hepatogenesis are well characterized [1]. Changes in gene expression during the postnatal/pre-pubertal period are less well understood [3], especially with regards to sex-biased gene expression. During early mouse postnatal development, rapid growth of the body and somatic organs occurs and slows down as the animal ages. The developmental decreases in somatic growth and in the expression of Igf, Mest, Peg appear to be regulated by the size and not the age of the animal per se, as seen in studies where the anti-thyroid drug propylthiouracil is used to inhibit body growth [10]
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