The online version of this article (doi:10.1186/s13075-017-1260-x) contains supplementary material, which is available to authorized users.
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.
Additional file 1: Figure S1. Genome browser screen shots. Chromatin organization around PTPN2 and NFKBIL2 loci. (TIFF 20832 kb)
Additional file 2: Figure S3. Genome browser screen shots. Chromatin organization around the RUNX3 locus. (TIFF 10898 kb)
Additional file 3: Table S1. Summary of ChIA-PET peak regions intersecting with JIA-associated LD blocks. (XLSX 68 kb)
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)
Knowlton N, Jiang K, Frank MB, Aggarwal A, Wallace C, McKee R, Chaser B, Tung C, Smith L, Chen Y, et al. The meaning of clinical remission in polyarticular juvenile idiopathic arthritis: gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states. Arthritis Rheum. 2009;60:892–900. CrossRefPubMedPubMedCentral
Herlin MP, Petersen MB, Herlin T. Update on genetic susceptibility and pathogenesis in juvenile idiopathic arthritis.EMJ. Rheumatol. 2014;1:73–83.
Moncrieffe H, Hinks A, Ursu S, Kassoumeri L, Etheridge A, Hubank M, Martin P, Weiler T, Glass DN, Thompson SD, et al. Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. Pharmacogenet Genomics. 2010;20:665–76. CrossRefPubMedPubMedCentral
Jiang K, Zhu L, Buck MJ, Chen Y, Carrier B, Liu T, Jarvis JN. Disease-associated single-nucleotide polymorphisms from noncoding regions in juvenile idiopathic arthritis are located within or adjacent to functional genomic elements of human neutrophils and CD4+ T cells. Arthritis Rheumatol. 2015;67:1966–77. CrossRefPubMedPubMedCentral
The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature, 2012;489:57–74.
Gandin V, Sikstrom K, Alain T, Morita M, McLaughlan S, Larsson O, Topisirovic I. Polysome fractionation and analysis of mammalian translatomes on a genome-wide scale. J Vis Exp. 2014;17. doi: 10.3791/51455.
Li G, Cai L, Chang H, Hong P, Zhou Q, Kulakova EV, Kolchanov NA, Ruan Y. Chromatin interaction analysis with paired-end tag (ChIA-PET) sequencing technology and application. BMC Genomics. 2014;15 Suppl 12:S11. CrossRef
Ou YY, Mack GJ, Zhang M, Rattner JB. CEP110 and ninein are located in a specific domain of the centrosome associated with centrosome maturation. J Cell Sci. 2002;115:1825–35. PubMed
- Chromatin landscapes and genetic risk for juvenile idiopathic arthritis
James N. Jarvis
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II