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Vitamin C epigenetically controls osteogenesis and bone mineralization

Author

Listed:
  • Roman Thaler

    (Mayo Clinic
    Mayo Clinic
    Mayo Clinic)

  • Farzaneh Khani

    (Mayo Clinic)

  • Ines Sturmlechner

    (Mayo Clinic)

  • Sharareh S. Dehghani

    (Mayo Clinic)

  • Janet M. Denbeigh

    (Mayo Clinic)

  • Xianhu Zhou

    (Mayo Clinic)

  • Oksana Pichurin

    (Mayo Clinic)

  • Amel Dudakovic

    (Mayo Clinic
    Mayo Clinic)

  • Sofia S. Jerez

    (Mayo Clinic
    Mayo Clinic)

  • Jian Zhong

    (Mayo Clinic)

  • Jeong-Heon Lee

    (Mayo Clinic
    Mayo Clinic)

  • Ramesh Natarajan

    (Virginia Commonwealth University)

  • Ivo Kalajzic

    (UConn Health)

  • Yong-hui Jiang

    (Yale University School of Medicine)

  • David R. Deyle

    (Mayo Clinic)

  • Eleftherios P. Paschalis

    (Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital)

  • Barbara M. Misof

    (Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital)

  • Tamas Ordog

    (Mayo Clinic
    Mayo Clinic)

  • Andre J. Wijnen

    (University of Vermont)

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.

Suggested Citation

  • 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 Na, 2022. "Vitamin C epigenetically controls osteogenesis and bone mineralization," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32915-8
    DOI: 10.1038/s41467-022-32915-8
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    1. Stephanie P. DiTroia & Michelle Percharde & Marie-Justine Guerquin & Estelle Wall & Evelyne Collignon & Kevin T. Ebata & Kathryn Mesh & Swetha Mahesula & Michalis Agathocleous & Diana J. Laird & Gabri, 2019. "Author Correction: Maternal vitamin C regulates reprogramming of DNA methylation and germline development," Nature, Nature, vol. 576(7785), pages 1-1, December.
    2. Stephanie P. DiTroia & Michelle Percharde & Marie-Justine Guerquin & Estelle Wall & Evelyne Collignon & Kevin T. Ebata & Kathryn Mesh & Swetha Mahesula & Michalis Agathocleous & Diana J. Laird & Gabri, 2019. "Maternal vitamin C regulates reprogramming of DNA methylation and germline development," Nature, Nature, vol. 573(7773), pages 271-275, September.
    3. Michalis Agathocleous & Corbin E. Meacham & Rebecca J. Burgess & Elena Piskounova & Zhiyu Zhao & Genevieve M. Crane & Brianna L. Cowin & Emily Bruner & Malea M. Murphy & Weina Chen & Gerald J. Spangru, 2017. "Ascorbate regulates haematopoietic stem cell function and leukaemogenesis," Nature, Nature, vol. 549(7673), pages 476-481, September.
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