Control of Pro-Inflammatory Gene Programs by Regulated Trimethylation and Demethylation of Histone H4K20

Regulation of genes that initiate and amplify inflammatory programs of gene expression is achieved by signal-dependent exchange of co-regulator complexes that function to read, write and erase specific histone modifications linked to transcriptional activation or repression. Here, we provide evidence for an unexpected role of trimethylated histone H4 lysine 20 (H4K20me3) as a repression checkpoint that restricts expression of toll like receptor 4 (TLR4) target genes in macrophages. H4K20me3 is deposited at the promoters of a subset of these genes by the SMYD5 histone methyltransferase through its association with NCoR co-repressor complexes. Signal-dependent erasure of H4K20me3 is required for effective gene activation and is achieved by NF-KB-dependent delivery of the histone demethylase PHF2. Liver X receptors antagonize TLR4-dependent gene activation by maintaining NCoR/SMYD5-mediated repression. These findings reveal a histone H4K20 tri-methylation/de-methylation strategy that integrates positive and negative signaling inputs that control immunity and homeostasis. mRNA profiling from thioglycollate-elicited mouse macrophages treated with siRNA for Control, Smyd5 and Phf2 for 48 hours followed by 4 hours of LPS treatment.