Vitamin C epigenetically controls osteogenesis and bone mineralization

Nat Commun. 2022 Oct 6;13(1):5883. doi: 10.1038/s41467-022-32915-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Ascorbic Acid / pharmacology
  • Ascorbic Acid Deficiency* / genetics
  • Calcification, Physiologic / genetics
  • Cell Differentiation / genetics
  • Chromatin
  • DNA / metabolism
  • DNA Methylation
  • Histones / metabolism
  • Mice
  • Osteogenesis* / genetics

Substances

  • Chromatin
  • Histones
  • DNA
  • Ascorbic Acid