Rheumatoid arthritis (RA) is one of the autoimmune diseases, which is recently reported that epigenetic alterations are observed in its pathophysiological regulation. However, epigenetic regulatory mechanisms underlying RA pathogenesis are largely unknown. Therefore, we investigated epigenetic regulator(s) contributing RA pathogenesis in vivo by microarray gene expression analyses using experimental arthritis mouse model. As a result, epigenetic regulator Uhrf1 (Ubiquitin Like With PHD And Ring Finger Domains 1) mRNA was significantly increased in arthritis tissue. First, we show that limb mesenchymal cell-specific Uhrf1 conditional knockout mice (Uhrf1ΔLimb/ΔLimb ) using Prx1-Cre mice exhibit remarkably shortened long bones that have morphological deformities due to dysregulated chondrocyte differentiation and proliferation. Integrative analyses using RNA-seq and MBD-seq using primary cultured chondrocytes obtained from Uhrf1ΔLimb/ΔLimb mice identified Uhrf1’s target genes, such as Hspb1. Next, to understand the functions of Uhrf1 in arthritis, we generated synovial fibroblast (SF) specific Uhrf1 conditional knockout mice (Uhrf1ΔSF/ΔSF) using Col6a1-Cre mice. After arthritis induction, clinical and histological examinations showed that significant severe phenotypes were observed only in Uhrf1ΔSF/ΔSF mice, when compared with littermate control (Cont) mice. In addition, RNA-seq using primary SF obtained from Uhrf1ΔSF/ΔSF and Cont mice revealed that 171 genes were up-regulated more than 2 fold in Uhrf1ΔSF/ΔSF -SF compared with Cont-SF (p<0.05) without overlapping with genes increased in Uhrf1ΔLimb/ΔLimb chondrocytes. Gene ontology analysis on 171 genes revealed that these genes were significantly enriched in “rheumatoid arthritis” and “Cytokine-cytokine receptor interaction” pathways which contained 12 genes. These results indicate that Uhrf1 can orchestrate transcriptional activities of inflammation related various genes under arthritic conditions.
Taken together, Uhrf1 can govern cell type specific gene expression through its molecular function on DNA methylation and has an important role in musculoskeletal biology and diseases.