Reduced CpG methylation is associated with transcriptional activation of the bone-specific rat osteocalcin gene in osteoblasts

Alejandro Villagra, Jos Gutirrez, Roberto Paredes, Jos Sierra, Marcia Puchi, Maria Imschenetzky, Andre Van Wijnen, Jane Lian, Gary Stein, Janet Stein, Martin Montecino

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Chromatin remodeling of the bone-specific rat osteocalcin (OC) gene accompanies the onset and increase in OC expression during osteoblast differentiation. In osseous cells expressing OC, the promoter region contains two nuclease hypersensitive sites that encompass the elements that regulate basal tissue-specific and vitamin D-enhanced OC transcription. Multiple lines of evidence indicate that DNA methylation is involved in maintaining a stable and condensed chromatin organization that represses eukaryotic transcription. Here we report that DNA methylation at the OC gene locus is associated with the condensed chromatin structure found in cells not expressing OC. In addition, we find that reduced CpG methylation of the OC gene accompanies active transcription in ROS 17/2.8 rat osteosarcoma cells. Interestingly, during differentiation of primary diploid rat osteoblasts in culture, as the OC gene becomes increasingly expressed, CpG methylation of the OC promoter is significantly reduced. Inhibition of OC transcription does not occur by a direct mechanism because in vitro methylated OC promoter DNA is still recognized by the key regulators Runx/Cbfa and the vitamin D receptor complex. Furthermore, CpG methylation affects neither basal nor vitamin D-enhanced OC promoter activity in transient expression experiments. Together, our results indicate that DNA methylation may contribute indirectly to OC transcriptional control in osteoblasts by maintaining a highly condensed and repressed chromatin structure.

Original languageEnglish (US)
Pages (from-to)112-122
Number of pages11
JournalJournal of cellular biochemistry
Volume85
Issue number1
DOIs
StatePublished - Mar 19 2002

Keywords

  • CpG methylation
  • Osteocalcin
  • Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Villagra, A., Gutirrez, J., Paredes, R., Sierra, J., Puchi, M., Imschenetzky, M., Van Wijnen, A., Lian, J., Stein, G., Stein, J., & Montecino, M. (2002). Reduced CpG methylation is associated with transcriptional activation of the bone-specific rat osteocalcin gene in osteoblasts. Journal of cellular biochemistry, 85(1), 112-122. https://doi.org/10.1002/jcb.10113