title: Histone ADP-ribosylation facilitates gene transcription by directly remodeling nucleosomes.
abstract: The packaging of DNA into nucleosomes imposes obstacles on gene transcription, and histone-modifying and nucleosome-remodeling complexes work in concert to alleviate these obstacles so as to facilitate transcription. Emerging evidence shows that chromatin-associated poly(ADP-ribose) polymerase 1 (PARP-1) and its enzymatic activity facilitate inflammatory gene transcription and modulate the inflammatory response in animal models. However, the molecular mechanisms by which PARP-1 enzymatic activity facilitates transcription are not well understood. Here we show that through an intracellular signaling pathway, lipopolysaccharide (LPS) stimulation induces PARP-1 enzymatic activity and the ADP-ribosylation of histones at transcriptionally active and accessible chromatin regions in macrophages. In vitro DNase I footprinting and restriction endonuclease accessibility assays reveal that histone ADP-ribosylation directly destabilizes histone-DNA interactions in the nucleosome and increases the site accessibility of the nucleosomal DNA to nucleases. Consistent with this, LPS stimulation-induced ADP-ribosylation at the nucleosome-occupied promoters of il-1β, mip-2, and csf2 facilitates NF-κB recruitment and the transcription of these genes in macrophages. Therefore, our data suggest that PARP-1 enzymatic activity facilitates gene transcription through increasing promoter accessibility by histone ADP-ribosylation.
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Martinez-Zamudio
authors.forename: Hyo Chol
authors.initials: HC
authors.lastname: Ha
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008836:Micrococcal Nuclease / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009707:Nucleosomes / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D006657:Histones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009707:Nucleosomes; D000246:Adenosine Diphosphate Ribose; D004247:DNA; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D008836:Micrococcal Nuclease