Network Biology of the Skin [2]

Gene expression levels in normal tissues can differ substantially between individuals, due to inherited polymorphisms acting in cis or trans. Analysis of this variation across a population of genetically distinct individuals allows us to visualize a network of co-expressed genes under normal homeostatic conditions, and the consequences of perturbation by tissue damage or disease development. Here, we explore gene expression networks in normal adult skin from 470 genetically unique mice, and demonstrate the dependence of the architecture of signaling pathways on skin tissue location (dorsal or tail skin) and perturbation by induction of inflammation or tumorigenesis. Gene networks related to specific cell types, as well as signaling pathways including Sonic Hedgehog (Shh), Wnt, Lgr family stem cell markers, and keratins differed at these tissue sites, suggesting mechanisms for the differential susceptibility of dorsal and tail skin to development of skin diseases and tumorigenesis. The Pten tumor suppressor gene network is extensively rewired in premalignant tumors compared to normal tissue, but this response to perturbation is lost during malignant progression. We present a software package for eQTL network analysis and demonstrate how network analysis of whole tissues provides insights into interactions between cell compartments and signaling molecules. A backcross was generated using male Mus spretus and female FVB/N Hras-/- mice; female F1 hybrids were mated with male FVB/N Hras -/- or Hras -/+ mice to generate a backcross population that was either Hras +/+, +/-, or -/- as noted. Mice were aged to 8 weeks and a tail skin sample was snap frozen. This series contains only Hras +/+ and Hras +/- samples.

正常组织的基因表达水平在个体间存在显著差异，这源于顺式（cis）或反式（trans）作用的遗传多态性。对遗传背景各异的个体群体中的此类表达差异进行分析，可帮助我们可视化正常稳态条件下共表达基因的调控网络，以及组织损伤或疾病发生所带来的扰动效应。本研究针对470只遗传背景独特的正常成年小鼠的皮肤样本，解析其基因表达网络，并证实信号通路的架构依赖于皮肤组织的位置（背部皮肤或尾部皮肤），以及炎症诱导或肿瘤发生所带来的扰动。与特定细胞类型相关的基因网络，以及包括音猬因子（Sonic Hedgehog, Shh）、Wnt、Lgr家族干细胞标志物及角蛋白在内的信号通路，在两类皮肤组织中存在显著差异，这提示了背部与尾部皮肤对皮肤病及肿瘤发生易感性差异的潜在机制。与正常组织相比，前恶性肿瘤中的PTEN抑癌基因网络发生了广泛的重编程，但这种扰动应答在恶性进展过程中丧失。我们开发了一款用于表达数量性状基因座（eQTL）网络分析的软件包，并证实全组织网络分析可帮助我们解析细胞区室与信号分子间的相互作用。本研究以雄性斯浦瑞鼠（Mus spretus）与雌性FVB/N Hras-/-小鼠为亲本构建回交体系：将雌性F1杂交子代与雄性FVB/N Hras-/-或Hras-/+小鼠交配，得到基因型分别为Hras+/+、Hras+/-或Hras-/-的回交群体，具体基因型如前文所述。所有小鼠均饲养至8周龄，随后采集尾部皮肤样本并快速冷冻。本数据集仅包含Hras+/+与Hras+/-基因型的样本。