Sci Transl Med:生物标记有助提前发现多发性硬化和过敏症
DOI：10.1126/scitranslmed.aad2722 作者：M. Gustafsson
摘要 : 瑞典林雪平大学一项新的研究确认了调控多发性硬化和枯草热早期阶段的3种蛋白，这为在病人显示病兆前发现和预防这些免疫性疾病提供了可能颇有价值的生物学标记。
瑞典林雪平大学一项新的研究确认了调控多发性硬化和枯草热早期阶段的3种蛋白，这为在病人显示病兆前发现和预防这些免疫性疾病提供了可能颇有价值的生物学标记。研究人员说，他们的方法(即用基因组数据来模拟疾病的早期发展)或能帮助发现如癌症、心脏病、肥胖症或糖尿病等其它疾病的诊断性生物学标记。像癌症和免疫性疾病等常见病是在许多年甚或几十年中逐步演变而成的，这使得它们在病人出现症状之前尤其难以发现。为了在疾病开始前更好地理解和诊断它们，Mika Gustafsson和同事试图寻找与T细胞驱动疾病的早期发展有关的蛋白。为了研究培养的人类T细胞的随着时间推移的演变，他们组建了一个基因调控网络，这是一组细胞中的调控蛋白模型，这些调控蛋白共同支配着基因表达。将这一模型与发现在不同疾病中基因改变的基因组相关研究相结合，研究人员发现了3种转录因子(即控制某基因表达开与关的蛋白)，这些转录因子含有与疾病相关的基因变异。与多发性硬化和季节性过敏性鼻炎或枯草热的症状期相比，无症状期的这3种转录因子(即GATA3、MYB 和 MAF)及其预测的靶基因发生改变。通过研究罹患这两种免疫性疾病患者的T细胞，研究人员发现，在疾病缓解期，病人的这些转录因子的表达量低下，但在复发期，其靶基因则会有高亢的表达。这些结果表明，对这3种转录因子进行基因检测或能为早期发现和预防多发性硬化、枯草热及可能其它的T细胞驱动疾病开辟门径。
Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell–associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4+ T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell–associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell–mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, wheras their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.
来源： Science Translational Medicine 浏览次数：0