The NF-?B genomic landscape in lymphoblastoid B cells.

ABSTRACT: The nuclear factor ?B (NF-??) subunits RelA, RelB, cRel, p50, and p52 are each critical for B cell development and function. To systematically characterize their responses to canonical and noncanonical NF-?B pathway activity, we performed chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) analysis in lymphoblastoid B cell lines (LCLs). We found a complex NF-?B-binding landscape, which did not readily reflect the two NF-?B pathway paradigms. Instead, 10 subunit-binding patterns were observed at promoters and 11 at enhancers. Nearly one-third of NF-?B-binding sites lacked ?B motifs and were instead enriched for alternative motifs. The oncogenic forkhead box protein FOXM1 co-occupied nearly half of NF-?B-binding sites and was identified in protein complexes with NF-?B on DNA. FOXM1 knockdown decreased NF-?B target gene expression and ultimately induced apoptosis, highlighting FOXM1 as a synthetic lethal target in B cell malignancy. These studies provide a resource for understanding mechanisms that underlie NF-?B nuclear activity and highlight opportunities for selective NF-?B blockade.

SUBMITTER: Zhao B 

PROVIDER: S-EPMC4163118 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature