title: Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis.
abstract: Histone modifications are critical in regulating gene expression, cell cycle, cell proliferation, and development. Relatively few studies have investigated whether Helicobacter pylori, the major cause of human gastric diseases, affects histone modification. We therefore investigated the effects of H. pylori infection on histone modifications in a global and promoter-specific manner in gastric epithelial cells. Infection of gastric epithelial cells by wild-type H. pylori induced time- and dose-dependent dephosphorylation of histone H3 at serine 10 (H3 Ser10) and decreased acetylation of H3 lysine 23, but had no effects on seven other specific modifications. Different cag pathogenicity island (PAI)-containing-clinical isolates showed similar abilities to induce H3 Ser10 dephosphorylation. Mutation of cagA, vacA, nonphosphorylateable CagA mutant cagA(EPISA), or disruption of the flagella showed no effects, while deletion of the entire cagPAI restored the H3 Ser10 phosphorylation to control levels. Analysis of 27 cagPAI mutants indicated that the genes that caused H3 Ser10 dephosphorylation were similar to those that were previously found to induce interleukin-8, irrespective of CagA translocation. This effect was independent of ERK or p38 pathways and type I interferon signaling. Additionally, c-Jun and hsp70 gene expression was associated with this histone modification. These results demonstrate that H. pylori alters histone modification and host response via a cagA-, vacA-independent, but cagPAI-dependent mechanisms, which contribute to its persistent infection and pathogenesis.
authors.affiliation: Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Song-Ze
authors.initials: SZ
authors.lastname: Ding
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischer
authors.forename: Maria
authors.initials: M
authors.lastname: Kaparakis-Liaskos
authors.forename: George
authors.initials: G
authors.lastname: Liechti
authors.forename: D Scott
authors.initials: DS
authors.lastname: Merrell
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Grant
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ferrero
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Crowe
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Goldberg
mesh_terms: D000107:Acetylation; D000942:Antigens, Bacterial / Q000235:genetics / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000382:microbiology* / Q000473:pathology; D005753:Gastric Mucosa / Q000382:microbiology / Q000473:pathology*; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000473:pathology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D006657:Histones; C080866:cagA protein, Helicobacter pylori