Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis

• Published in: PloS one Vol. 5; no. 4; p. e9875
• Main Authors: Ding, Song-Ze, Fischer, Wolfgang, Kaparakis-Liaskos, Maria, Liechti, George, Merrell, D Scott, Grant, Patrick A, Ferrero, Richard L, Crowe, Sheila E, Haas, Rainer, Hatakeyama, Masanori, Goldberg, Joanna B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2010; Public Library of Science (PLoS)
• Subjects: Acetylation; Analysis; Antigens, Bacterial - genetics; Antigens, Bacterial - physiology; Antiulcer agents; Bacterial Proteins - genetics; Bacterial Proteins - physiology; Biological response modifiers; c-Jun protein; Carcinogens; Cell cycle; Cell proliferation; Cells, Cultured; Chemokines; Chromatin; Clinical isolates; Clonal deletion; Cytokines; Dephosphorylation; Disruption; Epithelial cells; Epithelial Cells - microbiology; Epithelial Cells - pathology; Flagella; Gastric Mucosa - microbiology; Gastric Mucosa - pathology; Gastroenterology and Hepatology/Gastrointestinal Cancers; Gastrointestinal diseases; Gene expression; Gene Expression Regulation; Genetic engineering; Genetic research; Genetics and Genomics/Epigenetics; Health aspects; Heat shock proteins; Helicobacter infections; Helicobacter Infections - pathology; Helicobacter pylori; Helicobacter pylori - pathogenicity; Histone H3; Histones - metabolism; Hsp70 protein; Humans; Immunology/Immunity to Infections; Infection; Infections; Infectious diseases; Infectious Diseases/Bacterial Infections; Infectious Diseases/Gastrointestinal Infections; Inflammation; Interferon; Interleukin 8; Ischemia; Kinases; Lysine; Medical research; Microbiology/Immunity to Infections; Mutants; Mutation; Pathogenesis; Pathogenicity; Pathogens; Phosphorylation; Polyamide-imides; Protein Processing, Post-Translational; Rodents; Serine; Signaling; Streptococcus infections; Transcription factors; Translocation; Trinucleotide repeats; United States > US; Virginia; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0009875

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.