Cindy Boer

Epigenomics in bone and cartilage disease | 51 1.2 ▲ Figure 3: Hypothetical model for RUNX2 regulation and expression . Several GWAS findings are linked to skeletal phenotypes located in the SUPT3H‐RUNX2 locus. OA=osteoarthritis; BMD=bone min- eral density; OPLL=ossification of the posterior longitudinal ligament of the spine; FM=facial morphol- ogy. (A) The locations of the GWAS findings coincide with possible active enhancers and promoter ele- ments in chondrogenic cells and osteoblast. In addition, near some of these enhancer and promoter elements, CTCF binding was found in Chip‐seq experiments in osteoblasts. For rs10948172, also meQTL effects on 4 CpG sites have been found in chondrogenic cells. (B) We hypothesize that the SNPs are lo- cated in long‐range enhancers, which regulate RUNX2 gene expression during osteoblast and chondro- genic differentiation. arise due to a difference in control of RUNX2 expression. Recent studies have shown that regulation of RUNX2 is tightly regulated by multiple epigenetic mechanisms, such as miR-204/211 and other miRNAs[131, 132], HDAC[133], and DNA methylation[123, 134]. Also, some of the genetic associa-tion signals near RUNX2 exert effects on epigenetics. For the osteoarthritis-associated SNP, rs10948172, it has been shown to operate as a methylation quantitative trait loci (mQTL) for 4 CpG sites in the RUNX2 locus[123, 134]. Nevertheless, the GWAS signals are positioned at a relative large distance from RUNX2, and chromatin interaction from regulatory region to gene promoter is needed. Using TAD localizations from the 3D ge- nome browser, we notice that all skeletal genetic RUNX2 signals are within one TAD. This makes physical interaction of enhancers—promoters through chromatin “looping” likely to occur within this region. Such loops are mostly regulated by several DNA bind- ing proteins such as cohesin and/or CTCF[135]. Using data from the ENCODE database, RUNX2 P1 and P2 promoter regions ( Figure 3 ). One can imagine that depending on the