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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Arthritis Research & Therapy 1/2017

Chromatin landscapes and genetic risk for juvenile idiopathic arthritis

Zeitschrift:
Arthritis Research & Therapy > Ausgabe 1/2017
Autoren:
Lisha Zhu, Kaiyu Jiang, Karstin Webber, Laiping Wong, Tao Liu, Yanmin Chen, James N. Jarvis
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13075-017-1260-x) contains supplementary material, which is available to authorized users.

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.
Zusatzmaterial
Additional file 1: Figure S1. Genome browser screen shots. Chromatin organization around PTPN2 and NFKBIL2 loci. (TIFF 20832 kb)
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Additional file 2: Figure S3. Genome browser screen shots. Chromatin organization around the RUNX3 locus. (TIFF 10898 kb)
13075_2017_1260_MOESM2_ESM.tiff
Additional file 3: Table S1. Summary of ChIA-PET peak regions intersecting with JIA-associated LD blocks. (XLSX 68 kb)
13075_2017_1260_MOESM3_ESM.xlsx
Additional file 4: Figure S2. Genes associated with these long-range interacting regions from CD4+ T cell ChIA-PET data. The genes associated with regions containing both H3K4me1 and H3K27ac marks have average higher FPKM than those genes that contained only H3K4me1 marks or those with no histone marks. (TIFF 17228 kb)
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Additional file 5: Table S2. Enriched biological functions of genes within JIA-associated LD blocks. (XLS 28 kb)
13075_2017_1260_MOESM5_ESM.xls
Literatur
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