An extended set of PRDM1/BLIMP1 target genes links binding motif type to dynamic repression

The transcriptional repressor B lymphocyte-induced maturation protein-1 (BLIMP1) regulates gene ex-pression and cell fate. The DNA motif bound by BLIMP1 in vitro overlaps with that of interferon regu-latory factors (IRFs), which respond to inflamma-tory/immune signals. At such sites, BLIMP1 and IRFs can antagonistically regulate promoter activity. In vitro motif selection predicts that only a subset of BLIMP1 or IRF sites is subject to antag-onistic regulation, but the extent to which antagon-ism occurs is unknown, since an unbiased assessment of BLIMP1 occupancy in vivo is lacking. To address this, we identified an extended set of promoters occupied by BLIMP1. Motif discov-ery and enrichment analysis demonstrate that multiple motif variants are required to capture BLIMP1 binding specificity. These are differentially associated with CpG content, leading to the obser-vation that BLIMP1 DNA-binding is methylation sen-sitive. In occupied promoters, only a subset of BLIMP1 motifs overlap with IRF motifs. Conversely, a distinct subset of IRF motifs is not enriched amongst occupied promoters. Genes linked to occupied promoters containing overlapping BLIMP1/IRF motifs (e.g. AIM2, SP110, BTN3A3) are shown to constitute a dynamic target set which is preferentially activated by BLIMP1 knock-down. These data confirm and extend the competitive model of BLIMP1 and IRF interaction