HDGFR2 regulates osteogenic differentiation by balancing histone crotonoylation and acetylation modifications [RNA-Seq]

Epigenetics regulates the expression of osteogenic genes and mediates the osteogenic differentiation of MSCs. It was found that hepatoma-derived growth factor (HDGFR2) is a histone methylated reader protein, which can recognize histone methylation modification and play an important "switch" role in gene transcriptional regulation. It is unclear whether HDGFR2 is involved in bone formation studies. Our study aims to investigate the effect of HDGFR2 on osteogenic differentiation and provide evidence for BMSCs as seed cells for tissue regeneration. We found that compared with the wild-type (WT) mice, the bone mass of the femur and the root furcation bone in HDGFR2-KO mice was significantly elevated to attenuate age-related bone loss. Compared with the BMSCs in WT mice, the cloning and osteogenic differentiation of BMSCs in HDGFR2-KO mice were significantly accelerated, and vice versa when HDGFR2 was overexpressed. GO analysis suggested that differential genes were mainly involved in osteoblast differentiation, ossification, collagen fiber tissue and mineralization. The bone defect repair ability of HDGFR2-KO mice was significantly enhanced compared to the control group. Moreover, the depletion of HDGFR2 suppressed periodontal bone loss. The HDGFR2 interacts with the active regulator of SIRT1 (AROS) and sirtuin family deacetylases to form a chromatin remodeling complex, and AROS regulated osteogenesis through combining with HDFGR2. The decreased ratio of H3K18 crotonylation to acetylation improved the transcription of osteogenic genes in HDGFR2 knockout BMSCs. Taken together, these data demonstrated that the knockdown of HDGFR2 could promote osteogenic differentiation and bone repair, providing a new theoretical basis for bone tissue regeneration.