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人类T细胞中调节基因的系统发现和扰动揭示了免疫网络的结构
2022-07-14 14:32

美国加州大学旧金山分校Alexander Marson和美国斯坦福大学Jonathan K. Pritchard团队共同合作,近期取得重要工作进展,他们的最新研究探明人类T细胞中调节基因的系统发现和扰动揭示了免疫网络的结构。相关论文2022年7月11日在线发表于《自然—遗传学》杂志上。

为了解基因表达中断如何通过网络渗透,研究人员必须首先绘制调控基因与其下游靶标之间的连接。

然而,研究人员缺乏对大多数基因上游调节因子的全面了解。在这里,研究人员开发了一种方法,用于系统地发现人类原代T细胞中关键免疫因子(IL2RA、IL-2 和 CTLA4)的上游调节因子。然后,研究人员使用CRISPR扰动、RNA-seq和ATAC-seq绘制了这些调节因子和推定的顺式调节元件的靶基因网络。这些调节器形成具有广泛反馈回路的密集互连网络。

此外,该网络富含与免疫相关的疾病变体和基因。这些结果提供了有关免疫相关疾病基因如何在T细胞中被调节的见解以及关于人类基因调节网络结构的更广泛的原理。

据介绍,基因调控网络确保重要基因以精确的水平表达。当基因表达受到充分干扰时,就会导致疾病。

附:英文原文

Title: Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks

Author: Freimer, Jacob W., Shaked, Oren, Naqvi, Sahin, Sinnott-Armstrong, Nasa, Kathiria, Arwa, Garrido, Christian M., Chen, Amy F., Cortez, Jessica T., Greenleaf, William J., Pritchard, Jonathan K., Marson, Alexander

Issue&Volume: 2022-07-11

Abstract: Gene regulatory networks ensure that important genes are expressed at precise levels. When gene expression is sufficiently perturbed, it can lead to disease. To understand how gene expression disruptions percolate through a network, we must first map connections between regulatory genes and their downstream targets. However, we lack comprehensive knowledge of the upstream regulators of most genes. Here, we developed an approach for systematic discovery of upstream regulators of critical immune factors—IL2RA, IL-2 and CTLA4—in primary human T cells. Then, we mapped the network of the target genes of these regulators and putative cis-regulatory elements using CRISPR perturbations, RNA-seq and ATAC-seq. These regulators form densely interconnected networks with extensive feedback loops. Furthermore, this network is enriched for immune-associated disease variants and genes. These results provide insight into how immune-associated disease genes are regulated in T cells and broader principles about the structure of human gene regulatory networks.

DOI: 10.1038/s41588-022-01106-y

Source: https://www.nature.com/articles/s41588-022-01106-y

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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