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Super-enhancers delineate disease-associated regulatory nodes in T cells

机译:超级增强剂描绘了T细胞中与疾病相关的调节节点

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摘要

Enhancers regulate spatiotemporal gene expression and impart cellspecific transcriptional outputs that drive cell identity'. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease(2-6). CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse 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. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages'. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis 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 the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.
机译:增强子调节时空基因表达并赋予驱动细胞特性的细胞特异性转录输出。超级增强子(SE)也称为拉伸增强子,是增强子的一个子集,对于与细胞身份和疾病遗传风险相关的基因特别重要(2-6)。 CD4(+)T细胞对于宿主防御和自身免疫至关重要。在这里,我们分析了小鼠T细胞SE的图谱,作为鉴定参与细胞规范的关键调控节点的一种无偏方式。我们发现,细胞因子和细胞因子受体是在T细胞中展现SE结构的基因的主要类别。尽管如此,编码Bach2(效应子分化的关键负调控因子)的基因座成为最突出的T细胞SE,揭示了一个网络,其中BACH2抑制了对T细胞生物学至关重要的SE相关基因。免疫介导的疾病(包括类风湿性关节炎)的与疾病相关的单核苷酸多态性比其他细胞谱系中的典型增强子或SE高得多。有趣的是,用Janus激酶(JAK)抑制剂tofacitinib处理T细胞不成比例地改变了具有SE结构的类风湿关节炎风险基因的表达。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,但受自身具有SE的“监护人”转录因子控制。因此,SE的枚举可以无偏地确定T细胞中的关键调节节点,而这些关键调节节点优选通过药理学干预进行调节。

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  • 来源
    《Nature》 |2015年第7548期|558-562|共5页
  • 作者单位

    NIAMSD, Lymphocyte Cell Biol Sect, NIH, Bethesda, MD 20892 USA;

    NIAMSD, Lymphocyte Cell Biol Sect, NIH, Bethesda, MD 20892 USA;

    NIAMS, Translat Immunol Sect, NIH, Bethesda, MD 20892 USA;

    NIAMSD, Lymphocyte Cell Biol Sect, NIH, Bethesda, MD 20892 USA;

    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA;

    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA;

    NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA;

    NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA;

    NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA;

    NIAMS, Translat Immunol Sect, NIH, Bethesda, MD 20892 USA;

    Univ Connecticut, Jackson Lab Genom Med, Farmington, CT 06030 USA|Univ Connecticut, Dept Genet & Dev Biol, Farmington, CT 06030 USA;

    Univ Connecticut, Jackson Lab Genom Med, Farmington, CT 06030 USA|Univ Connecticut, Dept Genet & Dev Biol, Farmington, CT 06030 USA;

    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA;

    NIAMS, La Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA;

    NIAMSD, Lymphocyte Cell Biol Sect, NIH, Bethesda, MD 20892 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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