Repression of gene expression by unphosphorylated NF-κB p65 through epigenetic mechanisms

Cells from a knock-in mouse expressing a NF-kappa B p65 mutant bearing an alanine instead of serine at position 276 (S276A) display a significant reduction of NF-kappa B-dependent transcription, even though the mutant p65 forms appropriate complexes that translocate normally to the nucleus and bind to DNA. Surprisingly, however, instead of the expected embryonic lethality from hepatocyte apoptosis seen in the absence of NF-kappa B activity, the S276A knock-in embryos die at different embryonic days due to variegated developmental abnormalities. We now demonstrate that this variegated phenotype is due to epigenetic repression resulting from the recruitment of histone deacetylases by the nonphosphorylatable form of NF-kappa B into the vicinity of genes positioned fortuitously near NF-kappa B-binding sites. Therefore, unphosphorylated nuclear NF-kappa B can affect expression of genes not normally regulated by NF-kappa B through epigenetic mechanisms.