HERPES-SIMPLEX VIRUS IMMEDIATE-EARLY PROTEINS ICP0 AND ICP4 ACTIVATE THE ENDOGENOUS HUMAN ALPHA-GLOBIN GENE IN NONERYTHROID CELLS

Globin genes are normally expressed only in erythroid cell lineages. H owever, we found that the endogenous alpha-globin gene is activated fo llowing infection of human fibroblasts and Beta cells with herpes simp lex virus (HSV), leading to accumulation of correctly initiated transc ripts driven by the alpha-globin promoter. The alpha 1- and alpha 2-gl obin genes were both induced, but expression of beta- or zeta-globin g enes could not be detected. Experiments using HSV mutants showed that null mutations in the genes encoding the viral immediate-early protein s ICP4 and ICP22 reduced induction approximately 10-fold, while loss o f ICPO function had a smaller inhibitory effect. Transient transfectio n experiments shelved that ICPO and ICP4 are each sufficient to trigge r detectable expression of the endogenous gene, while ICP22 had no det ectable effect in this assay. ICP4 also strongly enhanced expression o f transfected copies of the alpha 2-globin gene. In contrast, the aden ovirus E1a protein did not activate the endogenous gene and inhibited expression of the plasmid-borne alpha 2-globin gene. Previous studies have led to the hypothesis that chromosomal alpha-globin genes are sub ject to chromatin-dependent repression mechanism that prevents express ion in nonerythroid cells. Our data suggest that HSV ICPO and ICP4 eit her break or bypass this cellular gene silencing mechanism.