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BCOR regulates mesenchymal stem cell function by epigenetic mechanisms

Nature Cell Biology volume 11, pages 10021009 (2009) | Download Citation

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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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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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Affiliations

  1. Lab of Molecular Signaling, Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, USA.

    • Zhipeng Fan
    • , Jinhua Yu
    •  & Cun-Yu Wang
  2. Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, California 90033, USA.

    • Takayoshi Yamaza
    •  & Songtao Shi
  3. Department of Oral and Maxillofacial Surgery, University of San Francisco, San Francisco 94143, CA, USA.

    • Janice S. Lee
  4. Molecular Laboratory for Gene Therapy and Tooth Regeneration, Capital Medical University School of Stomatology, Beijing 100050, China.

    • Songlin Wang
  5. Department of Human Genetics, UCLA School of Medicine, Los Angeles, California 90095, USA.

    • Guoping 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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Cun-Yu Wang.

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https://doi.org/10.1038/ncb1913

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