This study investigates the mechanisms underlying the co-localization of transcription factors in different cell types. The authors focus on the transcription factor PU.1 and its interactions with lineage-determining factors in macrophages and B cells. They find that PU.1 collaborates with small sets of lineage-determining transcription factors to establish cell-specific binding sites, which are associated with promoter-distal H3K4me1-marked genomic regions. PU.1 binding initiates nucleosome remodeling and H3K4 monomethylation, creating sites that serve as "beacons" for additional factors, such as liver X receptors, which drive cell-specific gene expression and signal-dependent responses. The study suggests that simple combinations of lineage-determining transcription factors can specify the genomic sites responsible for both cell identity and cell type-specific responses to diverse signaling inputs.This study investigates the mechanisms underlying the co-localization of transcription factors in different cell types. The authors focus on the transcription factor PU.1 and its interactions with lineage-determining factors in macrophages and B cells. They find that PU.1 collaborates with small sets of lineage-determining transcription factors to establish cell-specific binding sites, which are associated with promoter-distal H3K4me1-marked genomic regions. PU.1 binding initiates nucleosome remodeling and H3K4 monomethylation, creating sites that serve as "beacons" for additional factors, such as liver X receptors, which drive cell-specific gene expression and signal-dependent responses. The study suggests that simple combinations of lineage-determining transcription factors can specify the genomic sites responsible for both cell identity and cell type-specific responses to diverse signaling inputs.