Clodfelter Karl H, Holloway Minita G, Hodor Paul, Park Soo-Hee, Ray William J, Waxman David J
Department of Biology, Boston University, 5 Cummington Street, Boston, Massachusetts 02215, USA.
Mol Endocrinol. 2006 Jun;20(6):1333-51. doi: 10.1210/me.2005-0489. Epub 2006 Feb 9.
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 secretion, with the transcription factor, signal transducer and activator of transcription (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, approximately 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 approximately 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.
哺乳动物肝脏中的性别二态性导致了生理、体内平衡以及类固醇和外源性化合物代谢方面的性别差异。许多性别依赖性肝脏基因受垂体生长激素（GH）分泌的性别差异调控，转录因子信号转导子和转录激活子（STAT5b）被认为介导了由脉动性的雄性血浆GH水平所引发的信号传导。目前，使用野生型和Stat5b基因敲除的雄性和雌性小鼠进行了一项大规模基因表达研究，以表征肝脏基因表达中的性别差异及其对STAT5b的依赖性。通过与具有23,574个特征的寡核苷酸微阵列进行竞争性杂交，确定了每种性别 - 基因型组合中各个肝脏RNA的相对丰度。在1603个小鼠基因中观察到肝脏表达存在显著的性别差异。在850个雄性中表达较高的基因中，767个（90%）在STAT5b缺陷型雄性中表达下调。此外，在753个以雌性为主表达的基因中，461个（61%）在STAT5b缺陷型雄性中表达上调。相比之下，约90%的性别依赖性基因在雌性中不受STAT5b缺陷的影响。因此：1）STAT5b对于性别依赖性肝脏基因表达至关重要，这是约1600个小鼠基因（占基因组的4%）的一个特征；2）雄性为主的肝脏基因表达需要STAT5b或STAT5b依赖性因子，它们以正向方式发挥作用；并且3）许多雌性为主的肝脏基因在雄性中以STAT5b依赖性方式受到抑制。几个STAT5b依赖性雄性基因编码转录抑制因子；这些可能包括直接抑制雄性肝脏中雌性为主基因的STAT5b靶标。几个雌性为主的抑制因子在STAT5b缺陷型雄性中升高；这些可能导致在缺乏STAT5b时雄性基因表达的主要缺失。
