The p65 (RelA) subunit of NF-kappa B interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression

Regulation of NF-kappaB transactivation function is controlled at several l evels, including interactions with coactivator proteins. Here we show that the transactivation function of NF-kappaB is also regulated through interac tion of the p65 (ReIA) subunit with histone deacetylase (HDAC) corepressor proteins. Our results show that inhibition of HDAC activity with trichostat in A (TSA) results in an increase in both basal and induced expression of a n integrated NF-kappaB-dependent reporter gene. Chromatin immunoprecipitati on (ChIP) assays show that TSA treatment causes hyperacetylation of the wil d-type integrated NF-kappaB-dependent reporter but not of a mutant version in which the NF-kappaB binding sites were mutated. Expression of HDAC1 and HDAC2 repressed tumor necrosis factor (TNF)-induced NF-kappaB-dependent gen e expression. Consistent with this, we show that HDAC1 and HDAC2 target NF- kappaB through a direct association of HDAC1 with the Re1 homology domain o f p65. HDAC2 does not interact with NF-kappaB directly but can regulate NF- kappaB activity through its association with HDAC1. Finally, we show that i nhibition of HDAC activity with TSA causes an increase in both basal and TN F-induced expression of the NF-kappaB-regulated interleukin-8 (IL-8) gene. Similar to the wild-type integrated NF kappaB-dependent reporter, ChIP assa ys showed that TSA treatment resulted in hyperacetylation of the IL-8 promo ter. These data indicate that the transactivation function of NF-kappaB is regulated in part through its association with HDAC corepressor proteins. M oreover, it suggests that the association of NF-kappaB with the HDAC1 and H DAC2 corepressor proteins functions to repress expression of NF-kappaB-regu lated genes as well as to control the induced level or expression of these genes.