Repression of gene expression by unphosphorylated NF-kappaB p65 through epigenetic mechanisms.
Cells from a "knock-in" mouse expressing a NF-kappaB p65 mutant bearing an alanine instead of serine at position 276 (S276A) display a significant reduction of NF-kappaB-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-kappaB 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-kappaB into the vicinity of genes positioned fortuitously near NF-kappaB-binding sites. Therefore, unphosphorylated nuclear NF-kappaB can affect expression of genes not normally regulated by NF-kappaB through epigenetic mechanisms.
Dong
Jie
J
Department of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Jimi
Eijiro
E
Zhong
Haihong
H
Hayden
Matthew S
MS
Ghosh
Sankar
S
D016475:3T3 Cells; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015153:Blotting, Western; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013489:Suppression, Genetic; D016019:Survival Analysis
D005136:Eye Proteins; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D052002:NF-kappa B p50 Subunit; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D012097:Repressor Proteins; D006655:Histone Deacetylases