image: In the physiological condition of skeletogenesis (left), SSCs maintain a quiescent state for orderly differentiation which is regulated by the epigenetic signature. Especially at this state, glycolysis in SSC is suppressed by Ptip reducing the H3K27ac level at the Pgk1 gene promoter region. However, under Ptip-deficiency (right), SSCs exit the quiescent state and actively proliferate and differentiate, which is due to increased H3K27ac occupancy at the promoter region of Pgk1 gene leading to elevated glycolysis. Consequently, disordered cell arrangement occurs in the growth plate patterning of long bones, resulting in skeletal dysplasia. The glycolytic pathway can be pharmaceutically targeted to ameliorate SSC and skeletal disorders under Ptip deficiency. RZ, rest zone; PZ, proliferative zone; HZ, hypertrophic zone; Pgk1, phosphoglycerate kinase 1; 2-DG, 2-Deoxy-D-glucose; 2-MeOE2, 2-Methoxyoestradiol; Tss, transcription start site; H3K27ac, histone H3 lysine 27 acetylation.
Credit: ©Science China Press
This study is led by Prof. Yi Bai (School & Hospital of Stomatology, Wuhan University), Prof. Haojian Zhang (School & Hospital of Stomatology, Wuhan University), Prof. Liang Kong (School of Stomatology, The Fourth Military Medical University).
The skeletal system harbors a stem cell population for the growth, maintenance and repair of the bone. Especially, Chan and colleagues have mapped skeletogenesis from a population of highly pure, skeletal stem cells (SSCs, CD45-Ter119-Tie2-CD51+Thy1-6C3-CD105-CD200+) to its downstream pre-bone cartilage and stromal progenitors (pBCSP) and BCSP, and later on revealed the distinct osteochondral SSC type orchestrating the long bone development located in the growth plate region. Epigenetic marks including histone modifications have increasingly been documented as crucial for defining stem cell identity and fate selection. However, cutting-edge knowledge on whether and how epigenetic mechanisms may regulate the quiescence and potency of SSC for safeguarding skeletal development is still limited.
In this study, Jianfei Liang et al. found endochondral SSC lineage output is involved in the physiological process of long bone development by flow cytometric analysis of the proportion of SSC, pBCSP and BCSP in the neonatal to the junior and the adult stage of mice. By concerted epigenetic and transcriptomic analyses of SSC and their descendent progenitor cells via integrating the chromatin immunoprecipitation sequencing (ChIP-seq) and the next-generation RNA sequencing (RNA-seq), they mapped the epigenetic landscape along the developmental trajectory of SSC.
Intriguingly, Ptip was identified as the candidate critical chromatin modifier that potentially determined SSC identity. They found loss of Ptip disrupted SSC function after tracing clones in the epiphyseal from Ptipflox/flox ;Ubc-ert2-cre;R26-confetti mice. Besides, Loss of Ptip especially in early progenitor cells (Col2+ chondroprogenitor cells), other than not in mature cells (Col10a1+cells), results in severe bone dysplasia due to SSC dysfunction.
Importantly, Ptip was discovered to suppress glycolysis of SSC via downregulating Phosphoglycerate kinase 1 (Pgk1), which was based on repressing histone H3 lysine 27 acetylation (H3K27ac) modification at the promoter region. Importantly, inhibition of glycolysis improved the function of SSC despite Ptip deficiency. Taken together, these findings establish a previously unrecognized epigenetic framework that Ptip governs the SSC quiescence and potency through metabolic control, paving an avenue for SSC-based treatments of bone developmental disorders.
Journal
Science Bulletin