Epigenetic regulation of osteoclast differentiation: possible involvement of Jmjd3 in the histone demethylation of Nfatc1.

Gene expression is controlled by epigenetic mechanisms such as histone acetylation and methylation, and recent studies have revealed that key developmental steps are regulated by the trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3). Using ChIP sequencing technology combined with real-time PCR, we here demonstrate that the H3K27me3 observed in the Nfatc1 gene in bone marrow-derived macrophages (BMMs) was markedly reduced in mature osteoclasts. Jumonji domain-containing 3 (Jmjd3), a H3K27 demethylase, was induced in bone marrow-derived macrophages and in the vicinity of the transcription start site (TSS) of nuclear factor-activated T cells (NFAT) c1 in response to receptor activator of nuclear factor-κB ligand (RANKL) stimulation. Gene silencing of the Jmjd3 gene by short hairpin RNA reduced demethylation of H3K27me3 at the TSS of Nfatc1 and suppressed RANKL-induced osteoclastogenesis. These results suggest that the demethylation of H3K27me3 in the Nfatc1 gene locus by Jmjd3 plays a critical role in RANKL-induced osteoclast differentiation.