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, Sofia S. Jerez, Jian Zhong, Jeong Heon Lee, Ramesh Natarajan, Ivo Kalajzic, Yong hui Jiang, David R. Deyle, Eleftherios P. Paschalis, Barbara M. Misof, Tamas Ordog, Andre J van Wijnen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number5883
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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