PU.1 and C/EBP(alpha) synergistically program distinct response to NF-kappaB activation through establishing monocyte specific enhancers.

Unraveling the complexity of transcriptional programs coded by different cell types has been one of the central goals of cell biology. By using genome-wide location analysis, we examined how two different cell types generate different responses to the NF-κB signaling pathway. We showed that, after TNF-α treatment, the NF-κB p65 subunit binds to distinct genome locations and subsequently induces different subsets of genes in human monocytic THP-1 cells versus HeLa cells. Interestingly, the differential p65 binding in two cell types correlates with preexisting cell type-specific enhancers before TNF-α stimulation, marked by histone modifications. We also found that two transcription factors, PU.1 and C/EBPα, appear to synergistically mediate enhancer creation and affect NF-κB target selection in THP-1 cells. In HeLa cells, coexpression of PU.1 and C/EBPα conferred TNF-α responsiveness to a subset of THP-1-specific NF-κB target genes. These results suggest that the diversity of transcriptional programs in mammalian cells arises, at least in part, from preexisting enhancers that are established by cell-specific transcription factors.