Deciphering the role of RUNX3 in Ankylosing Spondylitis
Ankylosing spondylitis (AS) is a common form of spinal inflammatory arthritis affecting about 200,000 individuals in the UK. Twin studies indicate that AS is highly heritable and it is likely that there are more than 100 genes involved. Among these associated genes, one is RUNX3 (involved in lymphocyte maturation). We have recently demonstrated that AS-associated single nucleotide polymorphisms (SNPs) upstream RUNX3 genomic locus have an effect on the function and the regulation of the gene.
Our primary goal is to decipher the precise mechanism(s) through which AS-associated SNPs at the RUNX3 locus alter gene expression and transcription in different cell types. This will help us to evaluate more completely the role of the RUNX3 locus as a pivotal epigenetic mechanism for the development of AS. We will investigate its role in the regulation of immune function by applying several cellular and molecular biology techniques that we have developed in our lab.
These results will allow us to define the gene regulatory networks specifically associated with AS. Our final goal is the investigation of potential pathogenic pathways and the development of interventional reagents as part of our early phase drug discovery programme for AS.
The approach described in relation to the RUNX3 locus is relevant to the investigation of many other loci that are genetically associated with AS.
Our group has successfully established different techniques in the lab. We routinely apply statistical methods to identify primary genetic associations, perform primary cell culture, electrophoretic mobility shift assay, chromatin immunoprecipitation, DNA/pull-down etc. Our group studies a range of fundamental and interlinked cell biology questions and will be involved in interacting with clinical members (Nuffield Orthopaedic Centre).
We also have close collaborations with:
- Professor Bowness group, immunology of Ankylosing Spondylitis;
- Professor Oppermann group (Molecular biology, drug development and chemical biology);
- Dr Fischer (Mass Spectrometry, within the Target Discovery Institute)
The successful candidate will have the chance to acquire skills in all these different areas.
Relevant Publications (max 5)
- Investigation of a possible extended risk haplotype in the IL23R region associated with ankylosing spondylitis. Roberts AR, Vecellio M, Cortes A, Knight JC, Cohen CJ, Wordsworth BP. Genes Immun. 2017 Mar;18(2):105-108. doi: 10.1038/gene.2017.5
- ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations. Roberts AR, Appleton LH, Cortes A, Vecellio M, Lau J, Watts L, Brown MA, Wordsworth P. Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):558-561.
- The genetic association of RUNX3 with ankylosing spondylitis can be explained by allele-specific effects on IRF4 recruitment that alter gene expression. Vecellio M, Roberts AR, Cohen CJ, Cortes A, Knight JC, Bowness P, Wordsworth BP. Ann Rheum Dis. 2016 Aug;75(8):1534-40. doi: 10.1136/annrheumdis-2015-207490.
- An ankylosing spondylitis-associated genetic variant in the IL23R-IL12RB2 intergenic region modulates enhancer activity and is associated with increased Th1-cell differentiation. Roberts AR, Vecellio M, Chen L, Ridley A, Cortes A, Knight JC, Bowness P, Cohen CJ, Wordsworth BP. Ann Rheum Dis. 2016 Dec;75(12):2150-2156. doi: 10.1136/annrheumdis-2015-208640.
- Two adjacent single nucleotide polymorphisms in a 5’ RUNX3 regulatory region that are independently associated with ankylosing spondylitis have distinct cellular and molecular effects Vecellio M, Cortes A, Roberts AR, Cohen CJ, Knight JC, Bowness P, Wordsworth BP.