Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Genet. 2020 Mar;52(3):247-253. doi: 10.1038/s41588-020-0579-4. Epub 2020 Feb 17.
Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4 T cell regulatory elements. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity. 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.
遗传研究表明，自身免疫易感性变异在记忆 CD4 T 细胞调节元件中过度表达。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，对于解析自身免疫的遗传机制至关重要。在这里，我们通过在健康个体中进行深度 RNA-seq，在记忆 CD4 T 细胞激活的八个时间点上对遗传调控效应的动态进行了描述。我们发现了全基因组范围内广泛存在的、动态的等位基因特异性表达，其中等位基因的平衡随时间而变化。这些基因在自身免疫基因座中富集了四倍。我们在六个 HLA 基因内发现了普遍存在的动态调控效应。HLA-DQB1 等位基因有三种不同的转录调控程序之一。使用 CRISPR-Cas9 基因组编辑，我们证明了一个启动子变体是 HLA-DQB1 表达的 T 细胞特异性调控的原因。我们的研究表明，顺式调控元件中的遗传变异以依赖于淋巴细胞激活状态的方式影响基因表达，这导致了免疫反应的个体间复杂性。
