Requirement of an E1A-sensitive coactivator for long-range transactivation by the beta-globin locus control region.

Forsberg EC, Johnson K, Zaboikina TN, Mosser EA, Bresnick EH
J Biol Chem. 1999 274 (38): 26850-9

PMID: 10480893 · DOI:10.1074/jbc.274.38.26850

Four erythroid-specific DNase I-hypersensitive sites at the 5'-end of the beta-globin locus confer high-level transcription to the beta-globin genes. To identify coactivators that mediate long-range transactivation by this locus control region (LCR), we assessed the influence of E1A, an inhibitor of the CBP/p300 histone acetylase, on LCR function. E1A strongly inhibited transactivation of Agamma- and beta-globin promoters by the HS2, HS2-HS3, and HS1-HS4 subregions of the LCR in human K562 and mouse erythroleukemia cells. Short- and long-range transactivation mediated by the LCR were equally sensitive to E1A. The E1A sensitivity was apparent in transient and stable transfection assays, and E1A inhibited expression of the endogenous gamma-globin genes. Only sites for NF-E2 within HS2 were required for E1A sensitivity in K562 cells, and E1A abolished transactivation mediated by the activation domain of NF-E2. E1A mutants defective in CBP/p300 binding only weakly inhibited HS2-mediated transactivation, whereas a mutant defective in retinoblastoma protein binding strongly inhibited transactivation. Expression of CBP/p300 potentiated HS2-mediated transactivation. Moreover, expression of GAL4-CBP strongly increased transactivation of a reporter containing HS2 with a GAL4 site substituted for the NF-E2 sites. Thus, we propose that a CBP/p300-containing coactivator complex is the E1A-sensitive factor important for LCR function.

MeSH Terms (21)

Acetyltransferases Adenovirus E1A Proteins Animals DNA-Binding Proteins E1A-Associated p300 Protein Erythroid-Specific DNA-Binding Factors Globins Histone Acetyltransferases Humans Leukemia, Erythroblastic, Acute Locus Control Region Mice NF-E2 Transcription Factor NF-E2 Transcription Factor, p45 Subunit Nuclear Proteins Polymerase Chain Reaction Saccharomyces cerevisiae Proteins Trans-Activators Transcriptional Activation Transcription Factors Tumor Cells, Cultured

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