Regulated interaction between cis-regulatory elements orchestrates the PU.1 expression pattern. Lack of PU.1 expression in nonhematopoietic cells is due to the lack of activation of critical enhancer elements located upstream of the PU.1 gene. The intermediate PU.1 levels expressed in B cells are driven by the assembly of a B cell–specific transcription factor complex at the −14-kb URE, which includes E2A and FOXO1, and the formation of a PU.1 autoregulatory loop. However, this complex is obviously not able to activate additional cis elements in the PU.1 locus. In contrast, myeloid progenitors express C/EBPα which binds the URE, induces the activation of the −12-kb enhancer to allow formation of a second PU.1 autoregulatory loop and binding of additional PU.1-driven transcription factors, such as EGR2, to increase PU.1 expression levels. Black arrows indicate transcription factor interactions/noncoding RNA; red arrows, enhancer-promoter interactions.