Vitamin C epigenetically controls osteogenesis and bone mineralization

• Published in: Nature communications 2022-10, Vol.13 (1), p.5883-5883, Article 5883
• Main Authors: Thaler, Roman, Khani, Farzaneh, Sturmlechner, Ines, Dehghani, Sharareh S., Denbeigh, Janet M., Zhou, Xianhu, Pichurin, Oksana, Dudakovic, Amel, Jerez, Sofia S., Zhong, Jian, Lee, Jeong-Heon, Natarajan, Ramesh, Kalajzic, Ivo, Jiang, Yong-hui, Deyle, David R., Paschalis, Eleftherios P., Misof, Barbara M., Ordog, Tamas, van Wijnen, Andre J.
• Format: Article
• Language: English
• Subjects: 38; 38/39; 38/91; 49; 49/15; 49/23; 631/337/176/1988; 631/532/2074; 64; 64/60; 692/699/1702/295; Adipogenesis; Animals; Ascorbic acid; Ascorbic Acid - pharmacology; Ascorbic Acid Deficiency - genetics; Bone growth; Calcification, Physiologic - genetics; Cell differentiation; Cell Differentiation - genetics; Chromatin; Circuits; Collagen; Connective tissues; Demethylation; Deoxyribonucleic acid; Differentiation (biology); DNA; DNA - metabolism; DNA Methylation; Enhancers; Epigenetics; Genes; Histones; Histones - metabolism; Humanities and Social Sciences; Mice; Mineralization; multidisciplinary; Osteoblastogenesis; Osteogenesis; Osteogenesis - genetics; Phenotypes; Priming; Science; Science (multidisciplinary); Vitamin C; Vitamin deficiency; Vitamin E
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32915-8

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. For decades vitamin C’s primary function in bone has been attributed to its involvement in collagen synthesis. Here, the authors uncover that vitamin C’s central role in bone is to globally orchestrate osteogenesis via epigenetic mechanisms.