Gene Expression and Genetic Variation in Response to Endoplasmic Reticulum Stress in Human Cells
Gene Expression and Genetic Variation in Response to Endoplasmic Reticulum Stress in Human Cells
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DOI：
10.1016/j.ajhg.2010.03.017
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发表时间：
2010-05-14
影响因子：
9.8
通讯作者：
Spielman, Richard S.
中科院分区：
文献类型：
--
作者：
Dombroski, Beth A.;Nayak, Renuka R.;Spielman, Richard S.
内质网（ER）中未折叠或错误折叠蛋白质的积累导致称为“ER应激”的状况，其诱导未折叠蛋白质反应（UPR），这是一种复杂的细胞过程，包括许多基因表达的变化。ER不能恢复稳态与人类疾病有关。为了鉴定响应于ER应激的基因表达的潜在变化，我们在人B细胞中诱导ER应激，然后在10个时间点测量基因表达。我们通过研究来自60个无关人员的细胞来跟踪这些结果。我们重新发现了已知在ER应激反应中发挥作用的基因，并发现了数千个未知的基因。其中两种是VLDLR和INHBE，它们在B细胞和原代成纤维细胞中ER应激后表达显著增加。为了研究UPR和疾病易感性之间的联系，我们确定了与人类疾病相关的ER应激反应基因，并评估了ER应激反应的个体差异。许多UPR基因与孟德尔疾病（如Wolfram综合征）和复杂疾病（包括肌萎缩侧索硬化症和糖尿病）相关。来自两个独立样本的数据显示ER应激反应存在广泛的个体差异。对同卵双胞胎的进一步分析显示，双胞胎对内质网应激的反应具有显著的相关性，从而显示出个体间遗传变异的证据。这些结果对ER功能及其在疾病易感性中的作用的基本理解具有意义。
The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) results in the condition called "ER stress," which induces the unfolded protein response (UPR), a complex cellular process that includes changes in expression of many genes. Failure to restore homeostasis ill the ER is associated with human diseases. To identify the underlying changes in gene expression in response to ER stress, we induced ER stress in human B cells and then measured gene expression at ten time points. We followed up those results by studying cells from 60 unrelated people. We rediscovered genes that were known to play a role in the ER-stress response and uncovered several thousand genes that are not known to be involved. Two of these are VLDLR and INHBE, which showed significant increase in expression after ER stress in B cells and in primary fibroblasts. To study the links between UPR and disease susceptibility, we identified ER-stress-responsive genes that are associated with human diseases and assessed individual differences in the ER-stress response. Many of the U PR genes are associated with Mendelian disorders, such as Wolfram syndrome, and complex diseases, including amyotrophic lateral sclerosis and diabetes. Data from two independent samples showed extensive individual variability in ER-stress response. Additional analyses with monozygotic twins revealed significant correlations within twin pairs in their responses to ER stress, thus showing evidence for heritable variation among individuals. These results have implications for basic understanding of ER function and its role in disease susceptibility.