PPARγ forms a bridge between DNA methylation and histone acetylation at the C/EBPα gene promoter to regulate the balance between osteogenesis and adipogenesis of bone marrow stromal cells

The balance between osteogenesis and adipogenesis of bone marrow stromal cells is impaired in many human diseases. Knowledge of how to fine-tune this balance is of medical importance. CCAAT/enhancer binding protein (C/EBP) has been shown to regulate the balance between osteogenesis and adipogenesis of C3H10T1/2 cells, with epigenetic modifications of the C/EBP promoter playing an important role. The present study aimed to elucidate the underlying molecular mechanisms. The results showed that peroxisome proliferator-activated receptor (PPAR) binds the -1286bp/-1065bp region of the C/EBP promoter to activate C/EBP expression during osteogenesis and adipogenesis of C3H10T1/2 cells. DNA hypermethylation in the -1286bp/-1065bp region, observed at the terminal stage of osteogenesis, prevented PPAR binding, and then histone deacetylase1 (HDAC1) occupied this region to reduce the level of histone acetylation. We regulated the balance between osteogenesis and adipogenesis of mouse bone marrow stromal cells through modulation of DNA methylation and histone acetylation status. In addition, in bone marrow stromal cells from the glucocorticoid-induced osteoporosis (GIO) mouse, hypomethylation of CpG sites, higher binding of PPAR, acetylated histones 3 and 4, and reduced binding of HDAC1 in the -1286bp/-1065bp region of C/EBP promoter were observed, compared with normal mice. This study provides a deeper insight into the molecular mechanisms underlying the balance between osteogenesis and adipogenesis regulated by C/EBP in synergy with PPAR, and suggests a molecular model for how DNA methylation and histone acetylation are linked by PPAR to regulate differentiation of bone marrow stromal cells.