TY - JOUR
T1 - Vitamin C epigenetically controls osteogenesis and bone mineralization
AU - Thaler, Roman
AU - Khani, Farzaneh
AU - Sturmlechner, Ines
AU - Dehghani, Sharareh S.
AU - Denbeigh, Janet M.
AU - Zhou, Xianhu
AU - Pichurin, Oksana
AU - Dudakovic, Amel
AU - Jerez, Sofia S.
AU - Zhong, Jian
AU - Lee, Jeong Heon
AU - Natarajan, Ramesh
AU - Kalajzic, Ivo
AU - Jiang, Yong hui
AU - Deyle, David R.
AU - Paschalis, Eleftherios P.
AU - Misof, Barbara M.
AU - Ordog, Tamas
AU - van Wijnen, Andre J.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85139368937&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139368937&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-32915-8
DO - 10.1038/s41467-022-32915-8
M3 - Article
C2 - 36202795
AN - SCOPUS:85139368937
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5883
ER -