title: Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20.
abstract: Regulation of genes that initiate and amplify inflammatory programs of gene expression is achieved by signal-dependent exchange of coregulator complexes that function to read, write, and erase specific histone modifications linked to transcriptional activation or repression. Here, we provide evidence for the 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 corepressor complexes. Signal-dependent erasure of H4K20me3 is required for effective gene activation and is achieved by NF-κB-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 trimethylation/demethylation strategy that integrates positive and negative signaling inputs that control immunity and homeostasis.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Stender
authors.forename: Gabriel
authors.initials: G
authors.lastname: Pascual
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.forename: Kevin
authors.initials: K
authors.lastname: Do
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.forename: Michael
authors.initials: M
authors.lastname: Boutros
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000818:Animals; D002460:Cell Line; D056970:Co-Repressor Proteins / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D006657:Histones; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase