Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
Department of Biology, Chungnam National University, Daejeon, Republic of Korea.
Epigenetics Chromatin. 2024 Nov 26;17(1):35. doi: 10.1186/s13072-024-00561-7.
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 regulate other cellular processes.
We demonstrate that VprBP stimulates RANKL-induced differentiation of osteoclast precursor cells (OCPs) into mature osteoclasts by suppressing the expression of anti-osteoclastogenic genes through phosphorylation of threonine 120 on histone H2A (H2AT120p). H2AT120p is critical for VprBP function, because abrogating VprBP kinase activity toward H2AT120 transcriptionally reactivates anti-osteoclastogenic genes and significantly attenuates osteoclast differentiation. 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.
Our data reveal a previously unrecognized function of VprBP in supporting RANKL-induced osteoclast differentiation and the molecular mechanism underlying its action as a negative regulator of anti-osteoclastogenic genes.
骨重建是一个持续且平衡的过程，依赖于破骨细胞骨吸收和成骨细胞骨形成之间的动态平衡。在破骨细胞分化过程中，前成骨细胞生成基因和抗破骨细胞生成基因分别被正转录调节剂和负转录调节剂选择性靶向。VprBP，也称为 DCAF1，是一种新发现的激酶，在驱动表观遗传基因沉默和致癌转化方面发挥着重要作用。然而，目前尚不清楚 VprBP 是否参与调节其他细胞过程的信号通路。
我们证明 VprBP 通过磷酸化组蛋白 H2A 上的苏氨酸 120（H2AT120p）来抑制抗破骨细胞生成基因的表达，从而刺激 RANKL 诱导的破骨细胞前体细胞（OCP）向成熟破骨细胞分化。H2AT120p 对于 VprBP 功能至关重要，因为消除 VprBP 对 H2AT120 的激酶活性会转录重新激活抗破骨细胞生成基因，并显著抑制破骨细胞分化。与这一观点一致，我们的体内研究确立了 VprBP 介导的 H2AT120p 在过度活跃的破骨细胞引起的低骨量表型和骨质疏松症中的重要性。
我们的数据揭示了 VprBP 在支持 RANKL 诱导的破骨细胞分化中的先前未被认识的功能，以及其作为抗破骨细胞生成基因负调节剂的作用的分子机制。
