Abstract：
Stem cells remain in a quiescent state for long-term maintenance and preservation of potency; this process requires fine-tuning regulatory mechanisms. In this study, we identified the epigenetic landscape along the developmental trajectory of skeletal stem cells (SSCs) in skeletogenesis governed by a key regulator, Ptip (also known as Paxip1, Pax interaction with transcription-activation domain protein-1). Our results showed that Ptip is required for maintaining the quiescence and potency of SSCs, and loss of Ptip in type II collagen (Col2)+ progenitors causes abnormal activation and differentiation of SSCs, impaired growth plate morphogenesis, and long bone dysplasia. We also found that Ptip suppressed the glycolysis of SSCs through downregulation of phosphoglycerate kinase 1 (Pgk1) by repressing histone H3 lysine 27 acetylation (H3K27ac) at the promoter region. Notably, inhibition of glycolysis improved the function of SSCs despite Ptip deficiency. To the best of our knowledge, this is the first study to establish an epigenetic framework based on Ptip, which safeguards skeletal stem cell quiescence and potency through metabolic control. This framework is expected to improve SSC-based treatments of bone developmental disorders.
摘要：
干细胞保持在静止状态以长期维持和保存效力;该过程需要微调调节机制。在这项研究中,我们确定了沿着骨骼干细胞（SSC）的发育轨迹的表观遗传景观，Ptip（也称为Paxip1，Pax与转录激活域蛋白1相互作用）。我们的结果表明，Ptip是维持SSC的静止和效力所必需的，II型胶原（Col2）+祖细胞中Ptip的缺失导致SSC的异常活化和分化，受损的生长板形态发生，和长骨发育不良。我们还发现，Ptip通过在启动子区域抑制组蛋白H3K27ac，通过下调磷酸甘油酸激酶1（Pgk1）来抑制SSC的糖酵解。值得注意的是,尽管Ptip缺乏，但抑制糖酵解改善了SSC的功能。据我们所知,这是第一个基于Ptip建立表观遗传框架的研究，通过代谢控制保护骨骼干细胞的静止和效力。该框架有望改善基于SSC的骨发育障碍治疗。
