Super-enhancers delineate disease-associated regulatory nodes in T cells.
Super-enhancers delineate disease-associated regulatory nodes in T cells.
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DOI：
10.1038/nature14154
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发表时间：
2015-04-23
期刊：
影响因子：
64.8
通讯作者：
O'Shea, John J.
中科院分区：
文献类型：
--
作者：
Vahedi, Golnaz;Kanno, Yuka;Furumoto, Yasuko;Jiang, Kan;Parker, Stephen C. J.;Erdos, Michael R.;Davis, Sean R.;Roychoudhuri, Rahul;Restifo, Nicholas P.;Gadina, Massimo;Tang, Zhonghui;Ruan, Yijun;Collins, Francis S.;Sartorelli, Vittorio;O'Shea, John J.
增强子调节时空基因表达并赋予驱动细胞身份的细胞特异性转录输出。延伸增强子或超级增强子（SE）是增强子的子集，对于与细胞身份和疾病遗传风险相关的基因特别重要。CD 4 + T细胞对宿主防御和自身免疫至关重要。在此，我们分析了T细胞SE的图谱，作为识别参与细胞特化的关键调控节点的非偏倚手段。我们发现，细胞因子和细胞因子受体是T细胞中表现出SE结构的基因的优势类别。尽管如此，编码Bach 2的基因座，效应分化的关键负调节因子，作为最突出的T细胞SE出现，揭示了一个网络，其中SE相关的基因对T细胞生物学至关重要，被BACH 2抑制。免疫介导的疾病（包括类风湿性关节炎（RA））的疾病相关SNP相对于其他细胞谱系中的典型增强子（TE）或SE高度富集T细胞-SE。有趣的是，用Janus激酶（JAK）抑制剂托法替尼治疗T细胞，不成比例地改变了具有SE结构的RA风险基因的表达。总之，这些结果表明，在T细胞中具有SE结构的基因包含多种细胞因子和细胞因子受体，但由本身具有SE的“监护人”转录因子控制。因此，SE的计数允许无偏地确定T细胞中的关键调节节点，其优先通过药理学干预来调节。
Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity. Stretch- or super-enhancers (SEs) are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease. CD4+ T cells are critical for host defense and autoimmunity. Herein, we analyzed maps of T cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. This notwithstanding, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T cell SE, revealing a network wherein SE-associated genes critical for T cell biology are repressed by BACH2. Disease-associated SNPs for immune-mediated disorders, including rheumatoid arthritis (RA), were highly enriched for T cell-SEs versus typical enhancers (TEs) or SEs in other cell lineages. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor, tofacitinib, disproportionately altered the expression of RA risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a “guardian” transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.
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168.9
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Ferreira, Manuel A. R.;Matheson, Melanie C.;Duffy, David L.;Marks, Guy B.;Hui, Jennie;Le Souef, Peter;Danoy, Patrick;Baltic, Svetlana;Nyholt, Dale R.;Jenkins, Mark;Hayden, Catherine;Willemsen, Gonneke;Ang, Wei;Kuokkanen, Mikko;Beilby, John;Cheah, Faang;de Geus, Eco J. C.;Ramasamy, Adaikalavan;Vedantam, Sailaja;Salomaa, Veikko;Madden, Pamela A.;Heath, Andrew C.;Hopper, John L.;Visscher, Peter M.;Musk, Bill;Leeder, Stephen R.;Jarvelin, Marjo-Riitta;Pennell, Craig;Boomsma, Dorret I.;Hirschhorn, Joel N.;Walters, Haydn;Martin, Nicholas G.;James, Alan;Jones, Graham;Abramson, Michael J.;Robertson, Colin F.;Dharmage, Shyamali C.;Brown, Matthew A.;Montgomery, Grant W.;Thompson, Philip J.
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影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
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影响因子：
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作者：
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通讯作者：
Young RA