title: Chromatin landscapes and genetic risk for juvenile idiopathic arthritis.
abstract: The transcriptomes of peripheral blood cells in children with juvenile idiopathic arthritis (JIA) have distinct transcriptional aberrations that suggest impairment of transcriptional regulation. To gain a better understanding of this phenomenon, we studied known JIA genetic risk loci, the majority of which are located in non-coding regions, where transcription is regulated and coordinated on a genome-wide basis. We examined human neutrophils and CD4 primary T cells to identify genes and functional elements located within those risk loci.
  
  
  
  We analyzed RNA sequencing (RNA-Seq) data, H3K27ac and H3K4me1 chromatin immunoprecipitation-sequencing (ChIP-Seq) data, and previously published chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) data to characterize the chromatin landscapes within the known JIA-associated risk loci.
  
  
  
  In both neutrophils and primary CD4+ T cells, the majority of the JIA-associated linkage disequilibrium (LD) blocks contained H3K27ac and/or H3K4me1 marks. These LD blocks were also binding sites for a small group of transcription factors, particularly in neutrophils. Furthermore, these regions showed abundant intronic and intergenic transcription in neutrophils. In neutrophils, none of the genes that were differentially expressed between untreated patients with JIA and healthy children were located within the JIA-risk LD blocks. In CD4+ T cells, multiple genes, including HLA-DQA1, HLA-DQB2, TRAF1, and IRF1 were associated with the long-distance interacting regions within the LD regions as determined from ChIA-PET data.
  
  
  
  These findings suggest that genetic risk contributes to the aberrant transcriptional control observed in JIA. Furthermore, these findings demonstrate the challenges of identifying the actual causal variants within complex genomic/chromatin landscapes.
authors.affiliation: Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Lisha
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Graduate Program in Biological Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Karstin
authors.initials: K
authors.lastname: Webber
authors.affiliation: Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Laiping
authors.initials: L
authors.lastname: Wong
authors.affiliation: Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.|Genetics, Genomics, & Bioinformatics Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. jamesjar@buffalo.edu.|Genetics, Genomics, & Bioinformatics Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. jamesjar@buffalo.edu.
authors.forename: James N
authors.initials: JN
authors.lastname: Jarvis
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002648:Child; D002843:Chromatin / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D002843:Chromatin
keywords: CD4 + T cells; Epigenetic regulation; Functional elements; JIA; Neutrophils; SNP LD blocks