MITOGEN-ACTIVATED PROTEIN-KINASES ENHANCE LONG-RANGE ACTIVATION BY THE BETA-GLOBIN LOCUS-CONTROL REGION

The human beta-globin locus control region (LCR), which consists of fo ur erythroid-specific DNase I hypersensitive sites (HS1-HS4), function s over a long distance to control the transcription, chromatin structu re, and replication of the beta-globin genes. We have used stable tran sfection assays to show that activation of the mitogen-activated prote in (MAP) kinase pathway by low concentrations of the phorbol ester pho rbol 12-tetradecanoate 13-acetate (TPA) induces enhancer activity of t he LCR subregion HS2, but not HS3. Although HS2 enhancer activity is d iminished with increasing distance from the promoter, the relative lev el of induction by TPA is independent of HS2-promoter distance. Mutati on of cis-elements within HS2 reveals that the tandem-binding sites fo r the hematopoietic-specific transcription factor NF-E2 are required f or induction by TPA, and induction is conferred by expressing NF-E2 in an NF-E2-null cell line. These results show that MAP kinases target f actors functioning through the NF-E2 sites to enhance long-range trans activation by the LCR.