To investigate whether these trans-associated genes were bona fide IRF2 targets in monocytes, we performed chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) for primary monocytes from two healthy volunteers using the same experimental conditions to define IRF2 binding sites (table S5). We found that genes in trans to rs13149699 were significantly enriched for IRF2 binding in corresponding treatments (Fig. 4, F to H) with 8.0- and 8.7-fold relative increase in trans-associated genes residing in a 25-kb window around IRF2 binding sites after 2-hour LPS or IFN-γ, respectively, compared to those not in trans to rs13149699 (LPS2 P = 3.5 × 10−6, IFN-γ P = 1.9 × 10−6; Fisher’s exact test). It was apparent that not only were genes in trans to rs13149699 dependent on stimulation, but also that different stimuli elicited different genes in trans, implying that IRF2 regulation is similarly context-dependent. IRF2 is induced by IFN-γ and has both transcriptionally repressive and activating properties, antagonizing the action of IRF1 and modulating the IFN-induced immune response, notably to viral infection (31–33). Consistent with this, whereas most genes in trans to
