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Background:  Ankylosing Spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex aetiology and high heritability, involving more than 100 genetic associations. These include several AS-associated single nucleotide polymorphisms (SNPs) upstream of  RUNX3,  which encodes the multifunctional RUNT-related transcription factor (TF) 3. The lead associated SNP  rs6600247  ( p  = 2.6 × 10 −15 ) lies ∼13kb upstream of the  RUNX3  promoter adjacent to a c-MYC TF binding-site. The effect of  rs6600247  genotype on DNA binding and chromosome looping were investigated by electrophoretic mobility gel shift assays (EMSA), Western blotting-EMSA (WEMSA) and Chromosome Conformation Capture (3C).   Results:  Interrogation of ENCODE published data showed open chromatin in the region overlapping  rs6600247  in primary human CD14 +  monocytes, in contrast to the Jurkat T cell line or primary human T-cells. The  rs6600247  AS-risk allele is predicted to specifically disrupt a c-MYC binding-site. Using a 50bp DNA probe spanning  rs6600247  we consistently observed reduced binding to the AS-risk “C” allele of both purified c-MYC protein and nuclear extracts (NE) from monocyte-like U937 cells. WEMSA on U937 NE and purified c-MYC protein confirmed these differences ( n  = 3;  p  &amp;lt; 0.05). 3C experiments demonstrated negligible interaction between the region encompassing  rs6600247  and the RUNX3 promoter. A stronger interaction frequency was demonstrated between the  RUNX3  promoter and the previously characterised AS-associated SNP  rs4648889 .   Conclusion:  The lead SNP  rs6600247,  located in an enhancer-like region upstream of the  RUNX3  promoter, modulates c-MYC binding. However, the region encompassing  rs6600247  has rather limited physical interaction with the promoter of  RUNX3 . In contrast a clear chromatin looping event between the region encompassing  rs4648889  and the  RUNX3  promoter was observed. These data provide further evidence for complexity in the regulatory elements upstream of the  RUNX3  promoter and the involvement of  RUNX3  transcriptional regulation in AS.

Disruption of c-MYC Binding and Chromosomal Looping Involving Genetic Variants Associated With Ankylosing Spondylitis Upstream of the RUNX3 Promoter