The Regulatory Landscape of Osteogenic Differentiation

Authors

  • Anne-Mari Håkelien,

    1. Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital
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  • Jan Christian Bryne,

    1. Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital
    2. Genomics Core Facility, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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  • Kristine G. Harstad,

    1. Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital
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  • Susanne Lorenz,

    1. Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital
    2. Genomics Core Facility, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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  • Jonas Paulsen,

    1. Institute for Medical Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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  • Jinchang Sun,

    1. Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital
    2. Genomics Core Facility, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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  • Tarjei S. Mikkelsen,

    1. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts, USA
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  • Ola Myklebost,

    1. Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital
    2. Department of Molecular Bioscience, University of Oslo, Oslo, Norway
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  • Leonardo A. Meza-Zepeda

    Corresponding author
    1. Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital
    2. Genomics Core Facility, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
    • Correspondence: Leonardo A. Meza-Zepeda, Ph.D., Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Postboks 4953 Nydalen, NO-0424 Oslo, Norway. Telephone: 47-22781769; Fax: 47-22781795; e-mail: Leonardo.Meza-Zepeda@rr-research.no

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Abstract

Differentiation of osteoblasts from mesenchymal stem cells (MSCs) is an integral part of bone development and homeostasis, and may when improperly regulated cause disease such as bone cancer or osteoporosis. Using unbiased high-throughput methods we here characterize the landscape of global changes in gene expression, histone modifications, and DNA methylation upon differentiation of human MSCs to the osteogenic lineage. Furthermore, we provide a first genome-wide characterization of DNA binding sites of the bone master regulatory transcription factor Runt-related transcription factor 2 (RUNX2) in human osteoblasts, revealing target genes associated with regulation of proliferation, migration, apoptosis, and with a significant overlap with p53 regulated genes. These findings expand on emerging evidence of a role for RUNX2 in cancer, including bone metastases, and the p53 regulatory network. We further demonstrate that RUNX2 binds to distant regulatory elements, promoters, and with high frequency to gene 3′ ends. Finally, we identify TEAD2 and GTF2I as novel regulators of osteogenesis. Stem Cells 2014;32:2780–2793

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