Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event

Signal transducer and activator of transcription 5b (STAT5b) is a growth hormone (GH)-activated transcription factor and a master regulator of sexually dimorphic gene expression in the liver. Disruption of the GH hypothalamo-pituitary-liver axis controlling STAT5b activation can lead to metabolic dysregulation, steatosis, and liver cancer. Computational approaches were developed to identify factors that disrupt STAT5b function in a mouse liver gene expression compendium. A biomarker comprised of 144 STAT5b-dependent genes was derived using comparisons between wild-type male and wild-type female mice and between STAT5b-null and wild-type mice. Correlations between the STAT5b biomarker gene set and a test set comprised of expression datasets (biosets) with known effects on STAT5b function were evaluated using a rank-based test (the Running Fisher algorithm). Using a similarity p-value ≤ 10−4, the test achieved a balanced accuracy of 99% and 97% for detection of STAT5b activation or STAT5b suppression, respectively. The STAT5b biomarker gene set was then used to identify factors that activate (masculinize) or suppress (feminize) STAT5b function in an annotated mouse liver and primary hepatocyte gene expression compendium of ~1,850 datasets. Disruption of GH-regulated STAT5b is a common phenomenon in liver in vivo, with 5% and 29% of the male datasets, and 11% and 13% of the female datasets, associated with masculinization or feminization, respectively. As expected, liver STAT5b activation/masculinization occurred at puberty and suppression/feminization occurred during aging and in mutant mice with defects in GH signaling. A total of 70 genes were identified that have effects on STAT5b activation in genetic models in which the gene was inactivated or overexpressed. Other factors that affected liver STAT5b function were shown to include fasting, caloric restriction and infections. Together, these findings identify diverse factors that perturb the hypothalamo-pituitary-liver GH axis and disrupt GH-dependent STAT5b activation in mouse liver.

信号转导与转录激活因子5b（STAT5b）是一类受生长激素（GH）激活的转录因子，同时也是肝脏内性别二态性基因表达的核心调控因子。调控STAT5b激活的生长激素-下丘脑-垂体-肝脏轴发生紊乱，可引发代谢失调、肝脏脂肪变性乃至肝癌。研究团队开发了计算方法，在小鼠肝脏基因表达汇编中筛选可破坏STAT5b功能的调控因素。通过对比野生型雄性与野生型雌性小鼠、STAT5b缺失型（STAT5b-null）与野生型小鼠的基因表达谱，研究人员构建了包含144个STAT5b依赖型基因的生物标志物特征集。采用基于秩的检验方法——运行费舍尔算法（Running Fisher algorithm），评估了该STAT5b生物标志物基因集与已知可影响STAT5b功能的表达数据集（biosets）之间的相关性。当相似性p值≤10⁻⁴时，该检测方法在识别STAT5b激活与STAT5b抑制场景下，分别取得了99%与97%的平衡准确率。随后，研究团队利用该STAT5b生物标志物基因集，在包含约1850个数据集的注释型小鼠肝脏及原代肝细胞基因表达汇编中，筛选出可激活（即雄性化）或抑制（即雌性化）STAT5b功能的调控因子。体内肝脏中，受生长激素调控的STAT5b功能紊乱是一种普遍现象：5%与29%的雄性小鼠数据集、11%与13%的雌性小鼠数据集分别与雄性化或雌性化效应相关。正如预期，肝脏STAT5b激活/雄性化效应出现于青春期阶段，而STAT5b抑制/雌性化效应则发生于衰老过程，以及生长激素信号通路存在缺陷的突变小鼠体内。研究共鉴定出70个基因，在该基因被敲除或过表达的遗传模型中，这些基因可对STAT5b激活产生调控作用。其他可影响肝脏STAT5b功能的因素还包括禁食、热量限制与病原体感染。综上，本研究明确了多种可扰动生长激素-下丘脑-垂体-肝脏轴，并破坏小鼠肝脏内生长激素依赖型STAT5b激活的调控因子。