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 devel...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.展开更多
基金supported by the National Key Research and Development Program of China(2022YFA0103200)the National Natural Science Foundation of China(82325003,82230007,82200188,82270956 and 82171568)+1 种基金the National Defense Biotechnology Outstanding Young Talents Fund(01-SWKJYCJJ24)Shaanxi Province Innovation Capability Support Program Scientific and Technological Innovation Team(2023-CX-TD-69).
文摘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.
