STAT1 and IRF1 collaborate to induce interferon-γ (IFNγ) stimulated genes (ISGs), but the extent to which they act alone or together is unclear. The effect of single nucleotide polymorphisms (SNPs) on in vivo binding is also largely unknown. We show that IRF1 binds at proximal or distant ISG sites twice as often as STAT1, increasing to sixfold at the MHC class I locus. STAT1 almost always bound with IRF1, while most IRF1 binding events were isolated. Dual binding sites at remote or proximal enhancers distinguished ISGs that were responsive to IFNγ versus cell-specific resistant ISGs, which showed fewer and mainly single binding events. Surprisingly, inducibility in one cell type predicted ISG-responsiveness in other cells. Several dbSNPs overlapped with STAT1 and IRF1 binding motifs, and we developed methodology to rapidly assess their effects. We show that in silico prediction of SNP effects accurately reflects altered binding both in vitro and in vivo. These data reveal broad cooperation between STAT1 and IRF1, explain cell type specific differences in ISG-responsiveness, and identify genetic variants that may participate in the pathogenesis of immune disorders.

中文翻译：

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STAT1和IRF1增强子的性质以及SNP的影响。

STAT1和IRF1协同诱导干扰素-γ（IFNγ）刺激的基因（ISG），但它们单独或共同作用的程度尚不清楚。单核苷酸多态性（SNP）对体内结合的影响也是很大程度上未知。我们显示，IRF1在近端或远处ISG部位的结合是STAT1的两倍，在MHC I类基因座上增加至六倍。STAT1几乎总是与IRF1绑定，而大多数IRF1绑定事件是隔离的。远端或近端增强子的双重结合位点区分了对IFNγ响应的ISG，而对细胞特异性耐药的ISG则表现出更少的结合事件，且主要表现为单一结合事件。出人意料的是，一种细胞类型的可诱导性预测了其他细胞中的ISG反应性。几个dbSNP与STAT1和IRF1结合基序重叠，我们开发了可快速评估其作用的方法。我们表明，计算机模拟的SNP效果准确反映了体内和体外结合的改变。这些数据揭示了STAT1和IRF1之间的广泛合作，解释了ISG反应性中细胞类型的特异性差异，并鉴定了可能参与免疫疾病发病机制的遗传变异。