Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks.
Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks.
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DOI：
10.1038/s41588-022-01106-y
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发表时间：
2022-08
期刊：
影响因子：
30.8
通讯作者：
Garrido, Christian M.
中科院分区：
文献类型：
--
作者：
Freimer, Jacob W.;Shaked, Oren;Naqvi, Sahin;Sinnott-Armstrong, Nasa;Kathiria, Arwa;Chen, Amy F.;Cortez, Jessica T.;Greenleaf, William J.;Pritchard, Jonathan K.;Marson, Alexander;Garrido, Christian M.
基因调控网络确保重要基因以精确的水平表达。当基因表达受到足够的干扰时，它可能导致疾病。为了了解基因表达中断如何通过网络渗透，我们必须首先绘制调控基因及其下游靶点之间的连接。然而，我们对大多数基因的上游调节因子缺乏全面的了解。在这里，我们开发了一种方法，系统地发现上游调控的关键免疫因子-IL-2 RA，IL-2和CTLA-4-在原代人T细胞。然后，我们使用CRISPR扰动，RNA-seq和ATAC-seq绘制了这些调节因子的靶基因和推定的顺式调节元件的网络。这些调节器形成具有广泛反馈回路的密集互连网络。此外，该网络富含免疫相关疾病变体和基因。这些结果提供了关于免疫相关疾病基因如何在T细胞中调节的见解，以及关于人类基因调控网络结构的更广泛原则。
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.
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影响因子：
4.5
作者：
Cusanovich DA;Pavlovic B;Pritchard JK;Gilad Y
通讯作者：
Gilad Y
DOI：
10.1126/science.1179050
发表时间：
2009-10-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Amit I;Garber M;Chevrier N;Leite AP;Donner Y;Eisenhaure T;Guttman M;Grenier JK;Li W;Zuk O;Schubert LA;Birditt B;Shay T;Goren A;Zhang X;Smith Z;Deering R;McDonald RC;Cabili M;Bernstein BE;Rinn JL;Meissner A;Root DE;Hacohen N;Regev A
通讯作者：
Regev A
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK