VprBP regulates osteoclast differentiation via histone H2A phosphorylation
Bone remodeling is a continuous and balanced process which relies on the dynamic equilibrium between osteoclastic bone resorption and osteoblastic bone formation. During osteoclast differentiation, pro-osteoclastogenic and anti-osteoclastogenic genes are selectively targeted by positive and negative transcription regulators, respectively. VprBP, also known as DCAF1, is a recently identified kinase and plays an important role in driving epigenetic gene silencing and oncogenic transformation. However, nothing is currently known about a possible involvement of VprBP in signaling pathways that regulates other cellular processes. Here, we demonstrate that VprBP stimulates RANKL-induced osteoclast differentiation by attenuating the expression of anti-osteoclastogenic genes through phosphorylating histone H2A at threonine 120 (H2AT120p). H2AT120p is critical for VprBP function, because abrogating VprBP kinase activity toward H2AT120 significantly attenuates the differentiation of osteoclast precursor cells (OCPs) into mature osteoclasts. Consistent with this notion, our in vivo studies established the importance of VprBP-mediated H2AT120p in low bone mass phenotypes and osteoporosis caused by overactive osteoclasts. Together, our data reveal a previously unrecognized function of VprBP in supporting osteoclast differentiation and the molecular mechanism underlying its action as a negative regulator of anti-osteoclastogenic genes. Overall design: Comparative gene expression profiling analysis of RNA-seq data for BMDM  (Control shRNA, and VprBP1 shRNA).