Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci
Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci
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DOI：
10.1038/s41588-020-0579-4
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发表时间：
2020-02-17
期刊：
影响因子：
30.8
通讯作者：
Raychaudhuri, Soumya
中科院分区：
文献类型：
--
作者：
Gutierrez-Arcelus, Maria;Baglaenko, Yuriy;Raychaudhuri, Soumya
遗传学研究表明，自身免疫易感性变体在记忆性CD 4（+）T细胞调节元件中过度表达（1-3）。了解遗传变异如何影响不同T细胞生理状态下的基因表达对于解读自身免疫的遗传机制至关重要（4，5）。在这里，我们在健康个体中使用高深度RNA-seq在记忆CD 4（+）T细胞活化期间的八个时间点表征了遗传调控效应的动态。我们发现了基因组中广泛的、动态的等位基因特异性表达，其中等位基因的平衡随着时间的推移而变化。这些基因在自身免疫位点内富集四倍。我们发现广泛的动态调节作用在6个HLA基因。HLA-DQB 1等位基因具有三种不同的转录调控程序之一。使用CRISPR-Cas9基因组编辑，我们证明了启动子变体是T细胞特异性控制HLA-DQB 1表达的原因。我们的研究表明顺式调节元件的遗传变异以依赖于淋巴细胞活化状态的方式影响基因表达，从而导致免疫应答的个体间复杂性。在记忆性CD 4（+）T细胞活化期间的8个时间点进行的深度mRNA测序鉴定了广泛的动态等位基因特异性表达事件，这些事件在HLA和其他自身免疫性疾病位点中富集。
Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4(+) T cell regulatory elements(1-3). Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity(4,5). Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4(+) T cell activation with high-depth RNA-seq in healthy individuals. We discovered widespread, dynamic allele-specific expression across the genome, where the balance of alleles changes over time. These genes were enriched fourfold within autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes. HLA-DQB1 alleles had one of three distinct transcriptional regulatory programs. Using CRISPR-Cas9 genomic editing we demonstrated that a promoter variant is causal for T cell-specific control of HLA-DQB1 expression. Our study shows that genetic variation in cis-regulatory elements affects gene expression in a manner dependent on lymphocyte activation status, contributing to the interindividual complexity of immune responses.Deep mRNA sequencing at eight time points during memory CD4(+) T cell activation identifies widespread dynamic allele-specific expression events that are enriched in HLA and other autoimmune disease loci.