Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis
Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis
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DOI：
10.1152/physiolgenomics.00055.2007
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发表时间：
2007-09-19
影响因子：
4.6
通讯作者：
Waxman, David J.
中科院分区：
文献类型：
--
作者：
Clodfelter, Karl H.;Miles, Gregory D.;Waxman, David J.
哺乳动物肝脏的两性二态性影响影响肝脏生理的基因，包括炎症反应、疾病状态、类固醇和外来化合物的代谢。肝脏的性别特异性是由垂体生长激素（GH）分泌的性别差异决定的，而由男性血浆GH谱引发的细胞内信号传递需要转录因子信号转导和转录激活因子（STAT）5b。STAT5a是一种较小的肝脏STAT5形式>，与STAT5b 90%相同，也对两性二态血浆GH刺激有反应，但不能补偿STAT5b的缺失和相关的性别特异性肝脏基因表达的缺失。利用23,574个特征寡核苷酸微阵列和雄性和雌性小鼠（野生型和STAT5a失活小鼠）的肝脏进行了大规模的基因表达研究，以阐明肝脏基因表达是否依赖于STAT5a。2482个小鼠基因在表达上存在显著的性别差异，其中1045个在雄性中表达较高，1437个在雌性中表达较高。与STAT5b缺失的广泛影响相反，STAT5a缺失对肝脏性别特异性的影响有限但明确，1437个女性显性基因中有219个（15%）在STAT5a缺失的女性肝脏中特异性表达降低。对三种混合或近交系野生型小鼠的肝脏rna进行分析，鉴定出1028个性别二态基因，包括393个雌性优势基因，其中89个（23%）需要STAT5a才能在雌性肝脏中正常表达。这些发现强调了STAT5a在女性肝脏中调节性别特异性基因表达的重要性，与STAT5b形成鲜明对比，后者的主要作用仅限于男性肝脏。
Sexual dimorphism in mammalian liver impacts genes affecting hepatic physiology, including inflammatory responses, diseased states, and the metabolism of steroids and foreign compounds. Liver sex specificity is dictated by sex differences in pituitary growth hormone (GH) secretion, with the transcription factor signal transducer and activator of transcription (STAT)5b required for intracellular signaling initiated by the pulsatile male plasma GH profile. STAT5a, a minor liver STAT5 form >90% identical to STAT5b, also responds to sexually dimorphic plasma GH stimulation but is unable to compensate for the loss of STAT5b and the associated loss of sex-specific liver gene expression. A large-scale gene expression study was conducted using 23,574-feature oligonucleotide microarrays and livers of male and female mice, both wild-type and Stat5a-inactivated mice, to elucidate any dependence of liver gene expression on STAT5a. Significant sex differences in expression were found for 2,482 mouse genes, 1,045 showing higher expression in males and 1,437 showing higher expression in females. In contrast to the widespread effects of the loss of STAT5b, STAT5a deficiency had a limited but well-defined impact on liver sex specificity, with 219 of 1,437 female-predominant genes (15%) specifically decreased in expression in STAT5a-deficient female liver. Analysis of liver RNAs from wild-type mice representing three mixed or outbred strains identified 1,028 sexually dimorphic genes across the strains, including 393 female-predominant genes, of which 89 (23%) required STAT5a for normal expression in female liver. These findings highlight the importance of STAT5a for regulation of sex-specific gene expression specifically in female liver, in striking contrast to STAT5b, whose major effects are restricted to male liver.