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

• Autores: Golnaz Vahedi, Yuka Kanno, Yasuko Furumoto, Kan Jiang, Stephen C. J. Parker, Michael R. Erdos
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 520, Nº 7548, 2015, págs. 558-562
• Idioma: inglés
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• Resumen

  • Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity 1. 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 7. 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.