HLA等位基因特異性表達動態變化
作者：
小柯機器人發布時間：2020/2/21 16:26:41
美國哈佛醫學院Soumya Raychaudhuri研究團隊揭示，HLA和其他自免疫基因座等位基因特異性表達在T細胞活化過程中的動態變化。該項研究成果2020年2月17日發表於《自然—遺傳學》。
他們利用深度RNA-seq技術表徵了健康個體中記憶CD4 + T細胞活化的八個時間點的遺傳調控作用動力學。他們發現了整個基因組中廣泛、動態的等位基因特異性表達，其中等位基因的平衡會隨著時間而變化。這些基因在自身免疫基因座中富集了四倍。他們發現六個HLA基因中普遍的動態調節作用。HLA-DQB1等位基因具有三個不同的轉錄調控程序之一。
使用CRISPR–Cas9基因組編輯，他們證明了啟動子變異是T細胞特異性控制HLA-DQB1表達的原因。他們的研究表明，順式調控元件的遺傳變異以依賴淋巴細胞激活狀態的方式影響基因表達，從而導致免疫反應的個體複雜性。
據悉，遺傳研究表明，自身免疫易感性變異在記憶CD4 + T細胞調節元件中過量出現。理解遺傳變異如何影響不同T細胞生理狀態下的基因表達對於破譯自身免疫的遺傳機制至關重要。
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