Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093, Zurich, Switzerland.
Department of Genetic Medicine and Development, University of Geneva Medical School, and University Hospitals of Geneva, 1211, Geneva, Switzerland.
Nat Commun. 2017 Oct 31;8(1):1212. doi: 10.1038/s41467-017-01422-6.
Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations.
唐氏综合征（DS）主要由整个 21 号染色体三体引起（三体 21，T21）。在这里，我们使用 SWATH 质谱法来定量分析来自一对同卵双胞胎中 T21 不一致的成纤维细胞中的蛋白质丰度和蛋白质周转率，并对 11 名无关的 DS 个体和匹配的对照进行蛋白质表达谱分析。稳态和周转率蛋白质组数据的整合表明，在个体内和个体间，化学计量复合物成员的蛋白质特异性降解是 T21 基因剂量结果的主要决定因素。从基因组和转录组数据中看不出这种影响。该数据还表明，T21 导致广泛的蛋白质组重塑，影响所有染色体编码的蛋白质。最后，我们发现了广泛的、细胞器特异性的转录后效应，例如线粒体蛋白质组的显著下调，这有助于 T21 的特征。总的来说，我们提供了一个有价值的蛋白质组资源，以了解 DS 表型表现的起源。
