Vitamin C epigenetically controls osteogenesis and bone mineralization
Roman Thaler, Farzaneh Khani, Ines Sturmlechner, Sharareh S. Dehghani, Janet M. Denbeigh, Xianhu Zhou, Oksana Pichurin, Amel Dudakovic, Sofía Jerez, Jian Zhong, Jeong‐Heon Lee, Ramesh Natarajan, Ivo Kalajzić, Yong‐hui Jiang, David R. Deyle, Eleftherios P. Paschalis, Barbara M. Misof, Tamás Ördög, André J. van Wijnen
Abstract
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.