title: Chromatin-bound bacterial effector ankyrin A recruits histone deacetylase 1 and modifies host gene expression.
abstract: Control of host epigenetics is becoming evident as a mechanism by which symbionts and pathogens survive. Anaplasma phagocytophilum, an obligate intracellular bacterium, down-regulates multiple host defence genes where histone deacetylase 1 (HDAC1) binds and histone 3 is deacetylated at their promoters, including the NADPH oxidase component, CYBB. How HDAC1 is targeted to defence gene promoters is unknown. Ankyrin A (AnkA), an A. phagocytophilum type IV secretion system effector, enters the granulocyte nucleus, binds stretches of AT-rich DNA and alters transcription of antimicrobial defence genes, including down-regulation of CYBB. Here we found AnkA binds to a predicted matrix attachment region in the proximal CYBB promoter. Using the CYBB promoter as a model of cis-gene silencing, we interrogated the mechanism of AnkA-mediated CYBB repression. The N-terminus of AnkA was critical for nuclear localization, the central ANK repeats and C-terminus were important for DNA binding, and most promoter activity localized to the central ANK repeats. Furthermore, a direct interaction between AnkA and HDAC1 was detected at the CYBB promoter, and was critical for AnkA-mediated CYBB repression. This novel microbial manipulation of host chromatin and gene expression provides important evidence of the direct effects that prokaryotic nuclear effectors can exert over host transcription and function.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Rennoll-Bankert
authors.affiliation: Procter & Gamble Co., Cincinnati, OH, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Garcia-Garcia
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.|Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sara H
authors.initials: SH
authors.lastname: Sinclair
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.|Division of Medical Microbiology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Dumler
mesh_terms: D041081:Anaplasma phagocytophilum / Q000502:physiology*; D017487:Ankyrins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin; D015536:Down-Regulation; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D017487:Ankyrins; D002843:Chromatin; D008562:Membrane Glycoproteins; D037521:Virulence Factors; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D056284:Histone Deacetylase 1