Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
J Autoimmun. 2012 May;38(2-3):J144-55. doi: 10.1016/j.jaut.2011.11.004. Epub 2011 Nov 25.
In this study we investigated the contribution of gender to global gene expression in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy controls. We observed that, in contrast to the conventional approach, gender-based case-control comparisons resulted in genelists with significantly reduced heterogeneity in human populations. In addition, MS was characterized by significant changes both in the quantity and in the quality of the sex-specific genes. Application of stringent statistics defined gender-based signatures which classified a second independent MS population with high precision. The global unsupervised cluster analyses for 60 subjects showed that 29/31 female and 27/29 male samples were properly identified. Notably, MS was associated in women and in men with distinct gene signatures which however shared several molecular functions, biological processes and interactors. Issues regarding epigenetic control of gene expression appeared as the main common theme for disease, with a central role for the functional modules related to histone deacetylase, NF-kappaB and androgen receptor signaling. Moreover, in silico analyses predicted that the differential expression in MS women and men were depending on the transcription factor SP1. Specific targeting of this pathway by the bis-anthracycline WP631 impaired T cell responses in vitro and in vivo, and reduced the incidence and the severity of experimental autoimmune encephalomyelitis, indicating that SP1 dependent gene transcription sustains neuroinflammation. Thus, the gender-based approach with its reduced heterogeneity and the systems biology tools with the identification of the molecular and functional networks successfully uncovered the differences but also the commonalities associated to multiple sclerosis in women and men. In conclusion, we propose gender-based systems biology as a novel tool to gain fundamental information on disease-associated functional processes.
在这项研究中，我们研究了性别对多发性硬化症（MS）患者和健康对照者外周血单个核细胞中全球基因表达的贡献。我们观察到，与传统方法相反，基于性别的病例对照比较导致基因列表在人类群体中的异质性显著降低。此外，MS 表现出性别特异性基因数量和质量的显著变化。严格的统计学应用定义了基于性别的特征，这些特征可以高精度地对第二个独立的 MS 人群进行分类。对 60 名受试者进行的全局无监督聚类分析表明，31 名女性中的 29 名和 29 名男性中的 27 名样本被正确识别。值得注意的是，MS 在女性和男性中与独特的基因特征相关，但这些特征共享了几个分子功能、生物学过程和相互作用物。关于基因表达的表观遗传控制的问题似乎是疾病的主要共同主题，与组蛋白去乙酰化酶、NF-κB 和雄激素受体信号相关的功能模块起核心作用。此外，计算机分析预测，MS 女性和男性的差异表达取决于转录因子 SP1。双蒽环 WP631 对该途径的特异性靶向作用损害了体外和体内的 T 细胞反应，并降低了实验性自身免疫性脑脊髓炎的发生率和严重程度，表明 SP1 依赖性基因转录维持神经炎症。因此，基于性别的方法及其降低的异质性和系统生物学工具，用于识别分子和功能网络，成功地揭示了女性和男性多发性硬化症相关的差异和共性。总之，我们提出基于性别的系统生物学作为一种新的工具，可以获得与疾病相关的功能过程相关的基本信息。
