title: Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis.
abstract: Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease characterized by destructive vascular inflammation. Two prominent ANCA autoantigens are myeloperoxidase (MPO) and proteinase 3 (PR3), and transcription ofMPOandPRTN3, the genes encoding the autoantigens, is associated with disease activity. We investigated whether patients with AAV have alterations in histone modifications, particularly those associated with transcriptional activation, atMPOandPRTN3.
  
  
  
  We identified a network of genes regulating histone modifications that were differentially expressed in AAV patients compared to healthy controls. We focused on four genes (EHMT1andEHMT2,ING4, andMSL1) and found their expression correlated with expression ofMPOandPRTN3. Methylation of histone H3K9, catalyzed by EHMT1 and EHMT2 and associated with gene silencing, was most depleted atMPOandPRTN3in patients with active disease and the highestMPOandPRTN3expression. Acetylation of histone H4K16, modified by complexes containing ING4 and MSL1 and associated with gene activation, was most enriched atMPOandPRTN3in patients with active disease and the highestMPOandPRTN3expression. Methylation at H3K4, a mark of transcriptional activation, was enriched atMPOandPRTN3in patients and healthy controls.
  
  
  
  MPOandPRTN3in neutrophils of AAV patients with active disease have a distinct pattern of histone modifications, which implicates epigenetic mechanisms in regulating expression of autoantigen genes and suggests that the epigenome may be involved in AAV pathogenesis.
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Jiajin
authors.initials: J
authors.lastname: Yang
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.|Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Xian Jiaotong University, 157 Xiwu Road, Xian, Shaanxi 710004 People's Republic of China.
authors.forename: Heng
authors.initials: H
authors.lastname: Ge
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Poulton
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hogan
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Hu
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Britta E
authors.initials: BE
authors.lastname: Jones
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Candace D
authors.initials: CD
authors.lastname: Henderson
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McInnis
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Pendergraft
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.|Department of Genetics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Campus Box 7264, Chapel Hill, NC 27599 USA.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Ciavatta
mesh_terms: D000215:Acylation; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D053146:Myeloblastin / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009195:Peroxidase / Q000235:genetics*
chemical_list: D006657:Histones; D009195:Peroxidase; D053146:Myeloblastin
keywords: ANCA-associated vasculitis; Autoantigens; Epigenetics; Gene expression; Neutrophils