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Changes in gene expression from postnatal (3 wk and 4 wk) to young adult (8 wk) male and female mouse liver (Mus musculus)

ABSTRACT: Microarray analysis of male and female CD-1 mouse liver was carried out at 3, 4, and 8 wk of age to elucidate developmental changes in gene expression from the pre-pubertal period to young adulthood. A 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 genes subject to positive and negative regulation by pituitary hormone was also observed. Nine sex-specific transcription factors showed pubertal changes in expression and may contribute to the developmental changes that onset after 3-4 wk. Overall, 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE34782 | GEO | 2012/04/04

SECONDARY ACCESSION(S): PRJNA150335

REPOSITORIES: GEO

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Project description:Microarray analysis of male and female CD-1 mouse liver was carried out at 3, 4, and 8 wk of age to elucidate developmental changes in gene expression from the pre-pubertal period to young adulthood. A 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 HNF4M-NM-1, as determined in a liver-specific HNF4M-NM-1 knockout mouse model, while genes down regulated during this developmental period showed significant enrichment (p < E-65) for negative regulation by HNF4M-NM-1. Significant enrichment of the developmentally regulated genes in genes subject to positive and negative regulation by pituitary hormone was also observed. Nine sex-specific transcription factors showed pubertal changes in expression and may contribute to the developmental changes that onset after 3-4 wk. Overall, 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. Liver RNA isolated from the following six groups of CD-1 mice was used in the present study: 3 wk old male (M) mice (n = 10; 5 per each pool) and female (F) mice (n = 10; 5 per each pool); 4 wk old male mice (n = 12; 6 per each pool) and female mice (n = 12; 6 per each pool); 8 wk old male mice (n = 12; 6 per each pool) and female mice (n = 12; 6 per each pool). These RNA pools were used in seven separate sets of competitive hybridization experiments: 1) 3 wk M vs. 3 wk F; 2) 4 wk M vs. 4 wk F; 3) 8 wk M vs. 8 wk F; 4) 3 wk M vs. 8 wk M; 5) 4 wk M vs. 8 wk M; 6) 3 wk F vs. 8 wk F; 7) 4 wk F vs. 8 wk F. Fluorescent labeling of RNA and hybridization of the Alexa 555-labeled (green) and Alexa 647-labeled (red) aRNA samples to Agilent Mouse Gene Expression 4x44k v2 microarrays (Agilent Technology, Palo Alto, CA; catalog # G4846A-026655) were carried out, with dye swapping for each of the seven hybridization experiments to eliminate dye bias. Two microarrays, one for each mixed cDNA sample, were hybridized for each of the seven fluorescent reverse pairs, giving a total of 14 microarrays.

Project description:We identified genes expressed in mouse liver that are regulated by Cux2, a highly female-specific liver transcription factor whose expression is regulated by sex-dependent plasma GH patterns. Using adenovirus to overexpress Cux2 (Adeno-Cux2) in male liver, we show that Cux2 represses ~35% of male-biased genes and induces/de-represses ~35% of female-biased genes. Adeno-CMV was used as a control for adenoviral infection. (Published in Molec Cell Biology, TL Conforto et al, 2012) Liver RNA isolated from the following eight groups of mice was used in the present study: (1) 8 wk old untreated male (M) mice (n = 10; 5 per each pool); (2) 8 wk old untreated female mice (F) mice (n = 11; 5 or 6 per each pool); (3) 8 wk old male mice treated with Adeno-Cux2 and euthanized 5 days later (n = 12; 6 per each pool); (4) 8 wk old female mice treated with Adeno-Cux2 and euthanized 5 days later (n = 8; 4 per each pool); (5) 8 wk old male mice treated with Adeno-CMV and euthanized 5 days later (n = 13; 6 or 7 per each pool); (6) 8 wk old female mice treated with Adeno-CMV and euthanized 5 days later (n = 7; 3 or 4 per each pool); (7) 8 wk old male mice treated with Adeno-Cux2 and euthanized 3 days later (n=11; 5 or 6 per each pool); (8) 8 wk old male mice treated with Adeno-CMV and euthanized 3 days later (n=11; 5 or 6 per pool). These RNA pools were used in four separate sets of competitive hybridization experiments: 1) 8 wk untreated M vs. 8 wk untreated F; 2) 8 wk M + Ad-Cux2 (5 day) vs. 8 wk M + Ad-CMV (5 day); 3) 8 wk F + Ad-Cux2 (5 day) vs. 8 wk F + Ad-CMV (5 day); 4) 8 wk M + Ad-Cux2 (3 day) vs. 8 wk M + Ad-CMV (3 day). Fluorescent labeling of RNA and hybridization of the Alexa 555-labeled (green) and Alexa 647-labeled (red) RNA samples to Agilent Mouse Gene Expression 4x44k v1 microarrays (Agilent Technology, Palo Alto, CA; catalog # G4122F-014868) were carried out, with dye swapping for each of the three hybridization experiments to eliminate dye bias. Two microarrays, one for each mixed cDNA sample, were hybridized for each of the four fluorescent reverse pairs, giving a total of 8 microarrays.

Project description:A series of two color gene expression profiles obtained using Agilent 44K expression microarrays was used to examine sex-dependent and growth hormone-dependent differences in gene expression in rat liver. This series is comprised of pools of RNA prepared from untreated male and female rat liver, hypophysectomized (‘Hypox’) male and female rat liver, and from livers of Hypox male rats treated with either a single injection of growth hormone and then killed 30, 60, or 90 min later, or from livers of Hypox male rats treated with two growth hormone injections spaced 3 or 4 hr apart and killed 30 min after the second injection. The pools were paired to generate the following 6 direct microarray comparisons: 1) untreated male liver vs. untreated female liver; 2) Hypox male liver vs. untreated male liver; 3) Hypox female liver vs. untreated female liver; 4) Hypox male liver vs. Hypox female liver; 5) Hypox male liver + 1 growth hormone injection vs. Hypox male liver; and 6) Hypox male liver + 2 growth hormone injections vs. Hypox male liver. A comparison of untreated male liver and untreated female liver liver gene expression profiles showed that of the genes that showed significant expression differences in at least one of the 6 data sets, 25% were sex-specific. Moreover, sex specificity was lost for 88% of the male-specific genes and 94% of the female-specific genes following hypophysectomy. 25-31% of the sex-specific genes whose expression is altered by hypophysectomy responded to short-term growth hormone treatment in hypox male liver. 18-19% of the sex-specific genes whose expression decreased following hypophysectomy were up-regulated after either one or two growth hormone injections. Finally, growth hormone suppressed 24-36% of the sex-specific genes whose expression was up-regulated following hypophysectomy, indicating that growth hormone acts via both positive and negative regulatory mechanisms to establish and maintain the sex specificity of liver gene expression. For full details, see V. Wauthier and D.J. Waxman, Molecular Endocrinology (2008)

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Changes in gene expression from postnatal (3 wk and 4 wk) to young adult (8 wk) male and female mouse liver (Mus musculus)

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