Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities

Genome-scale studies have revealed extensive co-localization of transcription factors in a given cell type as well as substantial differences in the binding patterns of specific transcription factors between cell types. Several mechanisms have been proposed to explain these observations, including targeting of transcription factors to accessible chromatin marked by lysine 4-monomethylated histone H3 (H3K4me1) and interactions between transcription factors that enable nucleosome displacement. Here we demonstrate that collaborative interactions of PU.1 with small sets of macrophage- or B cell-lineage-determining transcription factors establish common and cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions in macrophages and B cells, respectively. PU.1 binding initiates nucleosome remodeling followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These sites are representative of locations that serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. In concert with analysis of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs.