Vitamin C epigenetically controls osteogenesis and bone mineralization.
Roman ThalerFarzaneh KhaniInes SturmlechnerSharareh S DehghaniJanet M DenbeighXianhu ZhouOksana PichurinAmel DudakovicSofia S JerezJian ZhongJeong-Heon LeeRamesh NatarajanIvo KalajzicYong-Hui JiangDavid R DeyleEleftherios P PaschalisBarbara M MisofTamas OrdogAndre J van WijnenPublished in: Nature communications (2022)
Vitamin C deficiency disrupts the integrity of connective tissues including bone. For decades this function has been primarily attributed to Vitamin C as a cofactor for collagen maturation. Here, we demonstrate that Vitamin C epigenetically orchestrates osteogenic differentiation and function by modulating chromatin accessibility and priming transcriptional activity. Vitamin C regulates histone demethylation (H3K9me3 and H3K27me3) and promotes TET-mediated 5hmC DNA hydroxymethylation at promoters, enhancers and super-enhancers near bone-specific genes. This epigenetic circuit licenses osteoblastogenesis by permitting the expression of all major pro-osteogenic genes. Osteogenic cell differentiation is strictly and continuously dependent on Vitamin C, whereas Vitamin C is dispensable for adipogenesis. Importantly, deletion of 5hmC-writers, Tet1 and Tet2, in Vitamin C-sufficient murine bone causes severe skeletal defects which mimic bone phenotypes of Vitamin C-insufficient Gulo knockout mice, a model of Vitamin C deficiency and scurvy. Thus, Vitamin C's epigenetic functions are central to osteoblastogenesis and bone formation and may be leveraged to prevent common bone-degenerating conditions.
Keyphrases
- bone mineral density
- gene expression
- bone regeneration
- mesenchymal stem cells
- soft tissue
- bone loss
- dna methylation
- bone marrow
- genome wide
- type diabetes
- signaling pathway
- dna damage
- metabolic syndrome
- single molecule
- skeletal muscle
- cell free
- adipose tissue
- heat stress
- long non coding rna
- genome wide analysis
- high fat diet induced