title: ARTD1 Suppresses Interleukin 6 Expression by Repressing MLL1-Dependent Histone H3 Trimethylation.
abstract: ADP-ribosyltransferase diphtheria-toxin like 1/poly(ADP-ribose) polymerase 1 (ARTD1/PARP1) is a chromatin-associated protein in the nucleus and plays an important role in different cellular processes such as regulation of gene transcription. ARTD1 has been shown to coregulate the inflammatory response by modulating the activity of the transcription factor nuclear factor κB (NF-κB), the principal regulator of interleukin 6 (IL-6), an important inflammatory cytokine implicated in a variety of diseases such as cancer. However, to what extent and how ARTD1 regulates IL-6 transcription has not been clear. Here, we show that ARTD1 suppresses lipopolysaccharide (LPS)-induced IL-6 expression in macrophages, without affecting the recruitment of the NF-κB subunit RelA to the IL-6 promoter and independent of its enzymatic activity. Interestingly, knockdown of ARTD1 did not alter H3 occupancy but increased LPS-induced trimethylation of histone 3 at lysine 4 (H3K4me3), a hallmark of transcriptionally active genes. We found that ARTD1 mediates its effect through the methyltransferase MLL1, by catalyzing H3K4me3 at the IL-6 promoter and forming a complex with NF-κB. These results demonstrate that ARTD1 modulates IL-6 expression by regulating the function of an NF-κB enhanceosome complex, which involves MLL1 and does not require ADP-ribosylation.
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.
authors.forename: Roberta
authors.initials: R
authors.lastname: Minotti
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich, Zurich, Switzerland.
authors.forename: Anneli
authors.initials: A
authors.lastname: Andersson
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland hottiger@vetbio.uzh.ch.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D013755:Tetradecanoylphorbol Acetate; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D015850:Interleukin-6; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051788:Myeloid-Lymphoid Leukemia Protein; D056484:Jumonji Domain-Containing Histone Demethylases; C485614:Kdm5b protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D013755:Tetradecanoylphorbol Acetate