Sex-specific mouse liver gene expression: genome-wide analysis of developmental changes from pre-pubertal period to young adulthood
Sex-specific mouse liver gene expression: genome-wide analysis of developmental changes from pre-pubertal period to young adulthood
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DOI：
10.1186/2042-6410-3-9
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发表时间：
2012-04-04
影响因子：
7.9
通讯作者：
Waxman, David J.
中科院分区：
文献类型：
--
作者：
Conforto, Tara L.;Waxman, David J.
背景：早期肝脏发育和肝发生过程中的转录转换是很好的特点。然而，基因表达的变化，在后期出生后/青春期前到青年期是不太好理解的，特别是关于性别特异性的基因expression.Methods：微阵列分析的雄性和雌性小鼠肝脏进行了3，4，和8周龄，以阐明从后期出生后/青春期前到青年期的基因表达的发育变化。在此发育时期，大量的性别偏向基因和性别非依赖基因发生了显著的变化。值得注意的是，与性别无关的基因参与细胞周期，染色体凝聚，DNA复制下调3周至8周，而与金属离子结合，离子转运和激酶活性相关的基因上调。大多数在成年肝脏中显示性别差异表达的基因在青春期之前没有显示性别差异，此时观察到性别特异性基因表达的广泛变化，主要是在男性中。因此，在男性肝脏中，76%的男性特异性基因上调，47%的女性特异性基因下调，从3至8周龄，而在女性肝脏67%的性别特异性基因的表达没有显着变化。在两种性别中，从3至8周上调的基因在由肝脏转录因子HNF 4 α正调控的基因组中显著富集（p < E-76），如在肝脏特异性HNF 4 α敲除小鼠模型中所确定的，而在该发育期下调的基因显示出由HNF 4 α负调控的显著富集（p < E-65）。还观察到发育调节基因在受垂体激素正调控和负调控的基因组中的显著富集。5个性别特异性转录调控因子在4 wk时表现出性别特异性表达（雄性特异性Ihh;雌性特异性Cdx 4、Cux 2、Tox和Trim 24），并且可能有助于导致在8周龄时全面获得肝脏性别特异性的发育变化。总的来说，在出生后肝脏发育过程中观察到的基因表达变化反映了肝脏生长的减速和特化肝脏的诱导功能，性别特异性基因表达的广泛变化主要发生在男性肝脏。
Background: Early 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.Methods: Microarray 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.Results: 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 sexspecific 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 HNF4 alpha, as determined in a liver-specific HNF4 alpha knockout mouse model, while genes down regulated during this developmental period showed significant enrichment (p < E-65) for negative regulation by HNF4 alpha. 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.Conclusions: 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 sexspecific gene expression primarily occurring in male liver.