DOI：10.1038/nature14154 中国科研用户发表 作者：Golnaz Vahedi
摘要 : 超级增强子是专门调控与细胞身份和遗传疾病风险相关的细胞功能的一类转录因子。
超级增强子是专门调控与细胞身份和遗传疾病风险相关的细胞功能的一类转录因子。对三个小鼠T-helper淋巴细胞子类中超级增强子的情况所做的这项研究，识别出了在细胞身份中起至关重要作用的节点，其中Bach2 位点(编码转录因子BACH2，后者是效应子分化的一个重要负调控因子)被发现是最显著的T-细胞超级增强子。Bach2 的扰动导致对“与超级增强子相关基因”和非编码RNA的表达产生一个优先效应。这项工作显示了可以将相关细胞类型的超级增强子图与人类遗传学相结合来发现药物目标基因的一个系统性方法。
Enhancers regulate spatiotemporal gene expression and impart cell-specific 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. 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 lineages7. 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.
来源： Nature 浏览次数：2