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

Abstract

The transcriptional repressor B lymphocyte-induced maturation protein-1 (BLIMP1) regulates gene expression and cell fate. The DNA motif bound by BLIMP1 in vitro overlaps with that of interferon regulatory factors (IRFs), which respond to inflammatory/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 antagonistic regulation, but the extent to which antagonism 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 discovery 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 observation that BLIMP1 DNA-binding is methylation sensitive. 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.

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

“…As expected, the predicted Blimp-1-binding motif, (N)(N)(T/A)GAAAGT, is similar to the previously identified sites from two independent studies, (A/C)AG(T/C)GAAAG(T/C)(G/T) 25 and GTGAAAGTand G(N) GAAAGT. 26 In addition, we found that, in MM cells, a large proportion of the genes that Aiolos bound directly had the consensus binding sequence TGAAACT (site 2), which is similar to the Blimp-1 consensus site. Another consensus binding sequence, A(N)AGGAA (site 1), was also found and is similar to that reported for Aiolos, ACAGGAAGT, in T cells.…”

N-terminally truncated FOXP1 protein expression and alternate internal FOXP1 promoter usage in normal and malignant B cells

“…Thus, it will be important to understand the likely oncogenic mechanisms controlling these transcriptional events. Significantly, BLIMP1 has been shown to bind the FOXP1 locus, 40 and thus BLIMP1 mutation 18 may drive ABC-DLBCL lymphomagenesis at least in part by mis-regulating FOXP1 isoform expression.…”

The Prdm family: expanding roles in stem cells and development

“…This sequence can also be recognized by interferon regulatory factors (IFRs, see Glossary, Box 1), and Prdm1 and IRFs can antagonistically regulate promoter activity (Kuo and Calame, 2004). More recently, DNA binding of Prdm1 was shown to be abrogated by CpG methylation, adding complexity to transcriptional regulation by this protein, and suggesting a model in which Prdm1 could be actively excluded from a subset of its target sites, once silencing at the level of DNA methylation has been established (Doody et al, 2011).…”