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Submitted on December 5, 2005
Accepted on January 30, 2006
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215; Department of Molecular Endocrinology, Merck Research Labs, West Point, PA 19486
* To whom correspondence should be addressed. E-mail: djw{at}bu.edu.
Sexual dimorphism in mammalian liver contributes to sex differences in physiology, homeostasis, and steroid and foreign compound metabolism. Many sex-dependent liver genes are regulated by sex differences in pituitary GH (GH) secretion, with the transcription factor STAT5b proposed to mediate signaling by the pulsatile, male plasma GH profile. Presently, a large-scale gene expression study was conducted using male and female mice, wild-type and Stat5b-inactivated, to characterize sex differences in liver gene expression and their dependence on STAT5b. The relative abundance of individual liver RNAs was determined for each sex-genotype combination by competitive hybridization to 23,574-feature oligonucleotide microarrays. Significant sex differences in hepatic expression were seen for 1603 mouse genes. Of 850 genes showing higher expression in males, 767 (90%) were down-regulated in STAT5b-deficient males. Moreover, of 753 genes showing female-predominant expression, 461 (61%) were up-regulated in STAT5b-deficient males. In contrast, 
90% of the sex-dependent genes were unaffected by STAT5b deficiency in females. Thus: 1) STAT5b is essential for sex-dependent liver gene expression, a characteristic of 1600 mouse genes (4% of the genome); 2) male-predominant liver gene expression requires STAT5b, or STAT5b-dependent factors, which act in a positive manner; and 3) many female-predominant liver genes are repressed in males in a STAT5b-dependent manner. Several of the STAT5b-dependent male genes encode transcriptional repressors; these may include direct STAT5b targets that repress female-predominant genes in male liver. Several female-predominant repressors are elevated in STAT5b-deficient males; these may contribute to the major loss of male gene expression seen in the absence of STAT5b.
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