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HLA等位基因特异性表达动态变化
2020-02-21 16:26

美国哈佛医学院Soumya Raychaudhuri研究团队揭示,HLA和其他自免疫基因座等位基因特异性表达在T细胞活化过程中的动态变化。该项研究成果2020217日发表于《自然—遗传学》。

他们利用深度RNA-seq技术表征了健康个体中记忆CD4 + T细胞活化的八个时间点的遗传调控作用动力学。他们发现了整个基因组中广泛、动态的等位基因特异性表达,其中等位基因的平衡会随着时间而变化。这些基因在自身免疫基因座中富集了四倍。他们发现六个HLA基因中普遍的动态调节作用。HLA-DQB1等位基因具有三个不同的转录调控程序之一。

使用CRISPR–Cas9基因组编辑,他们证明了启动子变异是T细胞特异性控制HLA-DQB1表达的原因。他们的研究表明,顺式调控元件的遗传变异以依赖淋巴细胞激活状态的方式影响基因表达,从而导致免疫反应的个体复杂性。

据悉,遗传研究表明,自身免疫易感性变异在记忆CD4 + T细胞调节元件中过量出现。理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破译自身免疫的遗传机制至关重要。

附:英文原文

Title: Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci

Author: Maria Gutierrez-Arcelus, Yuriy Baglaenko, Jatin Arora, Susan Hannes, Yang Luo, Tiffany Amariuta, Nikola Teslovich, Deepak A. Rao, Joerg Ermann, A. Helena Jonsson, Cristina Navarrete, Stephen S. Rich, Kent D. Taylor, Jerome I. Rotter, Peter K. Gregersen, Tonu Esko, Michael B. Brenner, Soumya Raychaudhuri

Issue&Volume: 2020-02-17

Abstract: 

Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4+ T cell regulatory elements1,2,3. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity4,5. 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.

DOI: 10.1038/s41588-020-0579-4

Source:https://www.nature.com/articles/s41588-020-0579-4#article-info

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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