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Arthritis Research and Therapy

, 19:57

First Online: 14 March 2017Received: 30 November 2016Accepted: 13 February 2017

Abstract

BackgroundThe 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.

MethodsWe 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.

ResultsIn 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.

ConclusionsThese 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.

KeywordsJIA Neutrophils CD4 + T cells SNP LD blocks Functional elements Epigenetic regulation AbbreviationsbpBase pairs

ChIA-PETChromatin interaction analysis by paired-end tag sequencing

ChIPseqChromatin immunoprecipitation-sequencing

FDRFalse discovery rate

FPKMfragments per kilobase of transcript

GWASGenome-wide association studies

JIAJuvenile idiopathic arthritis

LDLinkage disequilibrium

MIFMacrophage inhibitory factor

ncRNANon-coding RNA

rtPCRreverse transcriptase polymerase chain reaction

SNPSingle nucleotide polymorphism

SNAPSNP Annotation And Proxy search

TFTranscription factor

TFBSTranscription factor binding site

TNFtumor necrosis factor

TRAFtumor necrosis factor receptor-associated factor

TSStranscription start site

UCSCUniversity of California Santa Cruz

Electronic supplementary materialThe online version of this article doi:10.1186-s13075-017-1260-x contains supplementary material, which is available to authorized users.

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Author: Lisha Zhu - Kaiyu Jiang - Karstin Webber - Laiping Wong - Tao Liu - Yanmin Chen - James N. Jarvis

Source: https://link.springer.com/







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