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BCOR regulates mesenchymal stem cell function by epigenetic mechanisms

Nature Cell Biology volume 11, pages 1002–1009 (2009)Cite this article

Abstract

The BCL-6 co-repressor (BCOR) represses gene transcription by interacting with BCL-6 (Refs 1, 2). BCOR mutation is responsible for oculo-facio-cardio-dental (OFCD) syndrome, which is characterized by canine teeth with extremely long roots, congenital cataracts, craniofacial defects and congenital heart disease3,4,5. Here we show that BCOR mutation increased the osteo-dentinogenic potential of mesenchymal stem cells (MSCs) isolated from a patient with OFCD, providing a molecular explanation for abnormal root growth. AP-2α was identified as a repressive target of BCOR, and BCOR mutation resulted in abnormal activation of AP-2α. Gain- and loss-of-function assays suggest that AP-2α is a key factor that mediates the increased osteo-dentinogenic capacity of MSCs. Moreover, we found that BCOR maintained tissue homeostasis and gene silencing through epigenetic mechanisms. BCOR mutation increased histone H3K4 and H3K36 methylation in MSCs, thereby reactivating transcription of silenced target genes. By studying a rare human genetic disease, we have unravelled an epigenetic mechanism for control of human adult stem cell function.

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Figure 1: BCOR mutation results in enhanced osteo-dentinogenic potential of MSCs from a patient with OFCD.
Figure 2: Restoration of wild-type BCOR in MSC-O cells inhibited cell differentiation and proliferation.
Figure 3: BCOR mutation increases AP-2α expression in MSC-O cells.
Figure 4: AP-2α is a key mediator of the enhanced osteo-dentinogenic potential of MSCs by BCOR mutation.
Figure 5: BCOR represses AP-2α transcription by epigenetic mechanisms.

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Acknowledgements

This work was supported by the National Institute of Dental and Craniofacial Research Grants (R01DE1016513 and R01DE017684) to C.Y.W. (R21DE017632) and S.S., and the Shapiro Family Charitable Foundation. We thank Vivian Bardwell for reagents.

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Authors and Affiliations

  1. Division of Oral Biology and Medicine, Lab of Molecular Signaling, UCLA School of Dentistry,

    Zhipeng Fan, Jinhua Yu & Cun-Yu Wang

  2. Los Angeles, 90095, California, USA

    Zhipeng Fan, Jinhua Yu & Cun-Yu Wang

  3. Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, 90033, California, USA

    Takayoshi Yamaza & Songtao Shi

  4. Department of Oral and Maxillofacial Surgery, University of San Francisco, San Francisco, 94143, CA, USA

    Janice S. Lee

  5. Molecular Laboratory for Gene Therapy and Tooth Regeneration, Capital Medical University School of Stomatology, 100050, Beijing, China

    Songlin Wang

  6. Department of Human Genetics, UCLA School of Medicine, Los Angeles, 90095, California, USA

    Guoping Fan

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  1. Zhipeng Fan
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Contributions

Z.F., T.Y. and J.Y. performed experiments and prepared figures; J.S.L. prepared samples and directed the experiments; G.F. and S.W. assisted with the genetic analysis; S.S. and C.Y.W. designed the experiments and analysed the data; C.Y.W. wrote the manuscript.

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Correspondence to Cun-Yu Wang.

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Fan, Z., Yamaza, T., Lee, J. et al. BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat Cell Biol 11, 1002–1009 (2009). https://doi.org/10.1038/ncb1913

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