PU.1 is required for transcriptional activation of the Stat6 response element in the Igε promoter

Signal transducer and activator of transcription 6 (Stat6) has a crucial role in regulation of IL-4-induced gene responses. Stat6-binding sites are present in the promoters of both ubiquitously and cell-type-specifically expressed genes. The promoter regions of IL-4-inducible genes contain cis-acting elements for several transcription factors that act in concert with Stat6 and are also likely to modulate lineage-specific gene expression. We have observed that the Stat6 response element from the B-cell-specific Igepsilon promoter is readily activated upon IL-4 stimulation in B cells but not in non-hematopoietic cells. A minimal low-affinity PU.1-core-binding sequence (5'-AGAA-3') was identified within the Stat6 DNA-binding site in the Igepsilon promoter. Ectopic expression of the myeloid- and B-cell-specific transcription factor PU.1 restored the IL-4-inducibility of the Igepsilon-Stat6 response element in HepG2 cells, and the induction required an intact PU.1-binding sequence. Both the transactivation and the DNA-binding domains of PU.1 were required for induction of Stat6-mediated transcription. The co-operation between PU.1 and Stat6 in transactivation of the Igepsilon gene represents a molecular mechanism for the fine-tuning of cell-type-restricted expression of IL-4-induced gene responses.