SWI/SNF chromatin remodeling complex is obligatory for BMP2-induced, Runx2-dependent skeletal gene expression that controls osteoblast differentiation

Daniel W. Young, Jitesh Pratap, Amjad Javed, Brian Weiner, Yasuyuki Ohkawa, Andre Van Wijnen, Martin Montecino, Gary S. Stein, Janet L. Stein, Anthony N. Imbalzano, Jane B. Lian

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Development of bone tissue requires maturation of osteoblasts from mesenchymal precursors. BMP2, a member of the TGFβ superfamily, and the Runx2 (AML3/Cbfa1) transcription factor, a downstream BMP2 effector, are regulatory signals required for osteoblast differentiation. While Runx2 responsive osteogenic gene expression has been functionally linked to alterations in chromatin structure, the factors that govern this chromatin remodeling remain to be identified. Here, we address the role of the SWI/SNF chromatin remodeling enzymes in BMP2-induced, Runx2-dependent development of the osteoblast phenotype. For these studies, we have examined cal varial cells from wild-type (WT) mice and mice that are homozygous for the Runx2 null allele, as well as the C2C12 model of BMP2-induced osteogenesis. By the analysis of microarray data, we find that several components of the SWI/SNF complex are regulated during BMP2-mediated osteoblast differentiation. Brg1 is an essential DNA dependent ATPase subunit of the SWI/SNF complex. Thus, functional studies were carried out using a fibroblast cell line that conditionally expresses a mutant Brg1 protein, which exerts a dominant negative effect on SWI/SNF function. Our findings demonstrate that SWI/SNF is required for BMP2-induced expression of alkaline phosphatase (APase), an early marker reflecting Runx2 control of osteoblast differentiation. In addition, Brg1 is expressed in cells with in the developing skeleton of the mouse embryo as well as in osteoblasts ex vivo. Taken together these results support the concept that BMP2-mediated osteogenesis requires Runx2, and demonstrates that initiation of BMP2-induced, Runx2-dependent skeletal gene expression requires SWI/SNF chromatin remodeling complexes.

Original languageEnglish (US)
Pages (from-to)720-730
Number of pages11
JournalJournal of cellular biochemistry
Volume94
Issue number4
DOIs
StatePublished - Mar 1 2005

Keywords

  • AML3
  • Alkaline phosphatase
  • Bone formation
  • Cbfa1
  • Chromatin
  • Null mouse
  • Osteoblast differentiation
  • Runx2
  • SWI/SNF

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Young, D. W., Pratap, J., Javed, A., Weiner, B., Ohkawa, Y., Van Wijnen, A., Montecino, M., Stein, G. S., Stein, J. L., Imbalzano, A. N., & Lian, J. B. (2005). SWI/SNF chromatin remodeling complex is obligatory for BMP2-induced, Runx2-dependent skeletal gene expression that controls osteoblast differentiation. Journal of cellular biochemistry, 94(4), 720-730. https://doi.org/10.1002/jcb.20332