Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts, USA.
Mol Cell Biol. 2012 Feb;32(4):880-96. doi: 10.1128/MCB.06312-11. Epub 2011 Dec 12.
Sex-dependent pituitary growth hormone (GH) secretory patterns determine the sex-biased expression of >1,000 genes in mouse and rat liver, affecting lipid and drug metabolism, inflammation, and disease. A fundamental biological question is how robust differential expression can be achieved for hundreds of sex-biased genes simply based on the GH input signal pattern: pulsatile GH stimulation in males versus near-continuous GH exposure in females. STAT5 is an essential transcriptional mediator of the sex-dependent effects of GH in the liver, but the mechanisms that underlie its sex-dependent actions are obscure. Here we elucidate the dynamic, sex-dependent binding of STAT5 and the GH/STAT5-regulated repressor BCL6 to mouse liver chromatin genome wide, revealing a counteractive interplay between these two regulators of sex differences in liver gene expression. Our findings establish a close correlation between sex-dependent STAT5 binding and sex-biased target gene expression. Moreover, sex-dependent STAT5 binding correlated positively with sex-biased DNase hypersensitivity and H3-K4me1 and H3-K4me3 (activating) marks, correlated negatively with sex-biased H3-K27me3 (repressive) marks, and was associated with sex-differentially enriched motifs for HNF6/CDP factors. Importantly, BCL6 binding was preferentially associated with repression of female-biased STAT5 targets in male liver. Furthermore, BCL6 and STAT5 common targets but not BCL6 unique targets showed strong enrichment for lipid and drug metabolism. These findings provide a comprehensive, genome-wide view of the mechanisms whereby these two GH-regulated transcription factors establish and maintain sex differences affecting liver physiology and disease. The approaches used here to characterize sex-dependent STAT5 and BCL6 binding can be applied to other condition-specific regulatory factors and binding sites and their interplay with cooperative chromatin binding factors.
性别依赖性垂体生长激素（GH）分泌模式决定了雌雄激素在小鼠和大鼠肝脏中的表达模式，影响脂质和药物代谢、炎症和疾病。一个基本的生物学问题是，仅仅基于 GH 输入信号模式（男性中的脉冲性 GH 刺激与女性中的近乎连续的 GH 暴露），数百个性别偏向基因的差异表达如何能够实现。STAT5 是 GH 在肝脏中产生性别依赖性作用的重要转录介质，但它发挥性别依赖性作用的机制尚不清楚。在这里，我们阐明了 STAT5 的性别依赖性动态结合以及 GH/STAT5 调节的抑制剂 BCL6 在小鼠肝脏染色质基因组范围内的结合，揭示了这两种调节因子在肝脏基因表达性别差异中的拮抗相互作用。我们的研究结果建立了 STAT5 结合与性别偏向靶基因表达之间的密切相关性。此外，性别依赖性 STAT5 结合与性别偏向性 DNA 酶超敏性以及 H3-K4me1 和 H3-K4me3（激活）标记呈正相关，与性别偏向性 H3-K27me3（抑制）标记呈负相关，并且与 HNF6/CDP 因子的性别差异富集基序相关。重要的是，BCL6 结合与雄性肝脏中雌性偏向性 STAT5 靶基因的抑制优先相关。此外，BCL6 和 STAT5 的共同靶基因而不是 BCL6 独特靶基因显示出对脂质和药物代谢的强烈富集。这些发现提供了一个全面的、全基因组视角，说明了这两种 GH 调节的转录因子如何建立和维持影响肝脏生理学和疾病的性别差异。这里用于描述性别依赖性 STAT5 和 BCL6 结合的方法可以应用于其他条件特异性调节因子和结合位点及其与合作染色质结合因子的相互作用。
