Fig. 7

Model accounting for the opposite effects between synovium and cartilage of the risk allele on enhancer methylation and COLGALT2 expression. To be read in conjunction with Additional file 10. The causal variant has hypothetical alleles C (risk) and T (non-risk). In the synovium, the alleles differentially bind transcription factors TF1 and TF2; in the cartilage, they differentially bind transcription factors TF3 and TF4. Differential transcription factor binding leads to allele-specific enhancer methylation, resulting in quantitative differences in the binding of a common transcription factor (TF5). Low levels of bound TF5 lead to low levels of COLGALT2 transcription. In the synovium, allele C is more methylated at the enhancer than allele T, resulting in less TF5 binding to, and therefore relatively low transcription of, allele C. The opposite occurs in the cartilage. This matches our patient’s DNA methylation and COLGALT2 expression data. The model predicts that for both tissues, decreased enhancer methylation increases COLGALT2 expression and vice versa. This matches our epigenetic editing data of synovial cell line SW982 (this report) and of chondrocyte cell line Tc28a2 [8]