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Abstract Number: 1969

GENE Enhancers Associated with an Increase Risk of Developing JIA Fail to DOWN Regulate RUNX1 after CELL Stimulation

Annie Yarwood1, Kate Duffus2, Christopher Taylor3, Amanda McGovern2, Stephen Eyre4 and Wendy Thomson5, 1Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom, 2Arthritis Research UK Centre for Genetics and Genomics, University of Manchester, Manchester, United Kingdom, 3University of Manchester, Manchester, United Kingdom, 4NIHR Manchester Musculoskeletal Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, United Kingdom, 5Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Genetic disorders, genetics and juvenile idiopathic arthritis (JIA)

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Session Information

Date: Tuesday, October 23, 2018

Session Title: Genetics, Genomics and Proteomics Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

In recent years there have been tremendous strides in determining the genetic component of complex diseases, not least in Juvenile Idiopathic Arthritis (JIA). We now have 17 genetic loci robustly associated with an increased risk for developing JIA (1). In JIA, like all complex diseases, the regions of the genome harbouring genetic changes are found outside protein coding DNA, in regions of the genome shown to control gene expression, often sited some distance from the closest gene. One of these JIA associated regions, on chromosome 21q22, is labelled with the RUNX1gene, although the associated variants are situated over 450kb from the gene. We have previously demonstrated, through Capture HiC analysis, that the genomic region containing the JIA associated variants makes a physical contact with the RUNX1 promoter. The next challenge in this region, therefore, is to determine how a risk genetic background effects the expression of the gene, contributing to the susceptibility to JIA.

Methods:

B-lymphocyte cell lines, containing either a risk or protective JIA genetic background at the ‘RUNX1’ loci were interrogated for potential causative functional mechanism. Allele specific interactions were investigated using chromosome conformation capture (3C), enhancer activity (H3K4me1) with chromatin immunoprecipitation (ChIP), and the resultant expression of the RUNX1 gene analysed by qPCR in both stimulated (IL4/anti CD40) and unstimulated cell lines.

Results: The enhancer region associated with JIA interacts with the RUNX1 promoter in B-cell lines. A stimulation specific effect is observed in B-cell lines harbouring the protective alleles. In this protective context, prior to stimulation RUNX1 expression is higher than in the risk genotype with enhancer enrichment detected near the proximal promoter. After stimulation the interaction between the enhancer and RUNX1 promoter is much stronger, and whilst no enhancer enrichment was detected, this increased interaction frequency after stimulation corresponds to a sharp downregulation of RUNX1 expression. In contrast, the risk genotype showed no stimulation dependant change, maintaining both interaction and expression levels.

Conclusion: 3C and ChIP experiments were performed to investigate genotype and stimulation specific DNA-DNA and DNA-protein interactions and identify correlation with gene expression. These results suggest that the ability for B-cells to switch from relatively high expression of the RUNX1 transcript to low expression upon stimulation is crucial to an appropriate immune response


Disclosure: A. Yarwood, None; K. Duffus, None; C. Taylor, None; A. McGovern, None; S. Eyre, None; W. Thomson, None.

To cite this abstract in AMA style:

Yarwood A, Duffus K, Taylor C, McGovern A, Eyre S, Thomson W. GENE Enhancers Associated with an Increase Risk of Developing JIA Fail to DOWN Regulate RUNX1 after CELL Stimulation [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/gene-enhancers-associated-with-an-increase-risk-of-developing-jia-fail-to-down-regulate-runx1-after-cell-stimulation/. Accessed January 27, 2023.
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