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 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.
Doody
Gina M
GM
Section of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
Care
Matthew A
MA
Burgoyne
Nicholas J
NJ
Bradford
James R
JR
Bota
Maria
M
Bonifer
Constanze
C
Westhead
David R
DR
Tooze
Reuben M
RM
D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D018899:CpG Islands; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D017422:Sequence Analysis, DNA
D050835:Interferon Regulatory Factors; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1