Abstract
Trimethylation of histone H3 lysine 4 and lysine 27 (H3K4me3 and H3K27me3) at gene promoter regions critically regulates gene expression. Key developmental genes tend to exhibit changes in histone modification patterns from the H3K4me3/H3K27me3 bivalent pattern to the H3K4me3 monovalent pattern. Using comprehensive chromatin immunoprecipitation followed by sequencing in bone marrow-derived macrophages (BMMs) and mature osteoclasts, we found that cell surface adhesion molecule 1 (Cadm1) is a direct target of nuclear factor of activated T cells 1 (NFATc1) and exhibits a bivalent histone pattern in BMMs and a monovalent pattern in osteoclasts. Cadm1 expression was upregulated in BMMs by receptor activator of nuclear factor kappa B ligand (RANKL), and blocked by a calcineurin/NFATc1 inhibitor, FK506. Cadm1-deficient mice exhibited significantly reduced bone mass compared with wild-type mice, which was due to the increased osteoclast differentiation, survival and bone-resorbing activity in Cadm1-deficient osteoclasts. These results suggest that Cadm1 is a direct target of NFATc1, which is induced by RANKL through epigenetic modification, and regulates osteoclastic bone resorption in a negative feedback manner.
Highlights
Skeletal homeostasis is maintained in the balance between bone resorption and bone formation
Among the 33 identified genes, we focused on cell surface adhesion molecule 1 (Cadm1), which encodes a cell adhesion molecule belonging to the immunoglobulin superfamily [24]
Real-time PCR analysis revealed that Cadm1 expression was greatly increased during RANKL-stimulated osteoclastogenesis and positively correlated with elevated expression of Cathepsin K (Ctsk), a marker of osteoclast differentiation (Fig 1B)
Summary
Skeletal homeostasis is maintained in the balance between bone resorption and bone formation. An NFATc1 target Cadm is a negative regulator of osteoclastogenesis activates a wide range of intracellular signaling cascades that activate nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclast differentiation [5,6,7]. We previously demonstrated the bivalent to monovalent change of histone methylation at the promoter region of the NFATc1 gene during RANKL-induced osteoclastogenesis using chromatin immunoprecipitation followed by sequencing (ChIP-seq) [12]. NFATc1 is induced by RANKL stimulation downstream of calcium/calcineurin signaling [13], and plays key roles in osteoclastogenesis by regulating the expression of various osteoclast-related genes, such as Nfatc itself, Cathepsin K (Ctsk) and dendritic cell-specific transmembrane protein (Dc-stamp) [14,15,16]
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