Wy. Chen et al., REACTIVATION OF SILENCED, VIRALLY TRANSDUCED GENES BY INHIBITORS OF HISTONE DEACETYLASE, Proceedings of the National Academy of Sciences of the United Statesof America, 94(11), 1997, pp. 5798-5803
Retroviral and adeno-associated viral sequences can dramatically silen
ce transgene expression in mice. We now report that this repression al
so occurs in stably infected HeLa cells when the cells are grown witho
ut selection, Expression of a transduced lacZ gene (rAAV/CMVlacZ) is s
ilenced in greater than 90% of cells after 60 days in culture, Surpris
ingly, high-level expression can be reactivated by treating the cells
with sodium butyrate or trichostatin A but not with 5-azacytidine. Whe
n cell clones with integrated copies of rAAV/CMVlacZ were isolated, la
cZ expression was silenced in 80% of the clones; however, lacZ express
ion was reactivated in all of the silenced clones by treatment with bu
tyrate or trichostatin A. The two drugs also reactivated a silenced gl
obin gene construct (rAAV/HS2 alpha beta(AS3)) in stably infected K562
cells, Trichostatin A is a specific inhibitor of histone deacetylase;
therefore, we propose that hyperacetylation of histones after drug tr
eatment changes the structure of chromatin on integrated viral sequenc
es and relieves repression of transduced genes, The reactivation of si
lenced, transduced genes has implications for gene therapy, Efficient
viral gene transfer followed by drug treatment to relieve suppression
may provide a powerful combination for treatment of various genetic an
d infectious diseases.