The Center for Integrative Genomics, Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
PLoS Comput Biol. 2011 Jan 20;7(1):e1001054. doi: 10.1371/journal.pcbi.1001054.
The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, little is known about the global dysregulations caused by the WBS deletion. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genes that were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes in which the products localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish transcription modules, sets of genes coexpressed in this cell type. We identified those sets in which the average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways dysregulated in WBS patients, thus providing a testable set of additional candidates for genes and their interactions that modulate the WBS phenotypes.
由于对携带典型或非典型结构重排的个体，以及体外和动物研究的研究，与威廉姆斯-贝伦综合征（WBS）相关表型的遗传剖析正在取得进展。然而，对于 WBS 缺失引起的全局失调知之甚少。我们对 WBS 患者的皮肤成纤维细胞进行了转录组分析，并将其与匹配的对照进行了比较。我们确定了 868 个差异表达的基因，这些基因在细胞外基质基因、主要组织相容性复合体（MHC）基因以及定位于突触后膜的产物的基因中显著富集。然后，我们使用来自人类成纤维细胞的公共表达数据集来建立转录模块，即该细胞类型中共同表达的一组基因。我们确定了在 WBS 样本中平均基因表达发生改变的那些模块。失调的模块通常相互连接并共享多个共同基因，这表明受少数几个核心基因连接的复杂调节网络在 WBS 中受到干扰。这种模块化方法增加了识别 WBS 患者中失调途径的能力，从而为调节 WBS 表型的基因及其相互作用提供了一组可测试的额外候选基因。
