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BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets

Nature Neuroscience volume 15, pages 16271635 (2012) | Download Citation

Abstract

During neurogenesis, neural stem/progenitor cells (NPCs) undergo an irreversible fate transition to become neurons. The Notch pathway is important for this process, and repression of Notch-dependent Hes genes is essential for triggering differentiation. However, Notch signaling often remains active throughout neuronal differentiation, implying a change in the transcriptional responsiveness to Notch during the neurogenic transition. We identified Bcl6, an oncogene, as encoding a proneurogenic factor that is required for proper neurogenesis of the mouse cerebral cortex. BCL6 promoted the neurogenic conversion by switching the composition of Notch-dependent transcriptional complexes at the Hes5 promoter. BCL6 triggered exclusion of the co-activator Mastermind-like 1 and recruitment of the NAD+-dependent deacetylase Sirt1, which was required for BCL6-dependent neurogenesis. The resulting epigenetic silencing of Hes5 led to neuronal differentiation despite active Notch signaling. Our findings suggest a role for BCL6 in neurogenesis and uncover Notch-BCL6-Sirt1 interactions that may affect other aspects of physiology and disease.

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Acknowledgements

We thank G. Vassart for continuous support and interest, D. Christophe and members of the Vanderhaeghen lab and Institute for Interdisciplinary Research for helpful discussions and advice, F. Bollet-Quivogne (Fonds National de la Recherche Scientifique (FNRS) Logistic Scientist) of the Light Microscopy Facility for his support with imaging, R. Dalla-Favera (Columbia University) for generously sharing Bcl6−/− mice, F. Guillemot (National Institute of Medical Research) for kindly providing P19 cells, and G. Del Sal ((Laboratorio Nazionale CIB) Trieste) for the pCS2-NΔE construct, and B. Hassan, A. Soldano and K. De Backer for critically reading the manuscript. This work was funded by grants from the Belgian Queen Elizabeth Medical Foundation, the Fondations Pierre Clerdent and Roger de Spoelberch, the Action de Recherches Concertées Programs, the Interuniversity Attraction Poles Program, Belgian State, Federal Office for Scientific, Technical and Cultural Affairs, the Belgian FNRS and Fonds pour la Recherche Scientifique Médicale, and the Welbio and Programme d'Excellence CIBLES of the Walloon Region (to P.V.), as well as an EMBO Long-Term Fellowship (to L.T.) and a Marie Curie Fellowship (to T.B.). P.V. is Research Director, L.T. Postdoctoral Fellow, and J.v.d.A. and J.P. Research Fellows of the FNRS.

Author information

Author notes

    • Luca Tiberi
    •  & Jelle van den Ameele

    These authors contributed equally to this work.

Affiliations

  1. Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research, ULB Neuroscience Institute, Brussels, Belgium.

    • Luca Tiberi
    • , Jelle van den Ameele
    • , Jordane Dimidschstein
    • , Julie Piccirilli
    • , Adèle Herpoel
    • , Angéline Bilheu
    • , Jerome Bonnefont
    • , Tristan Bouschet
    •  & Pierre Vanderhaeghen
  2. Department of Neurology, Ghent University Hospital, Ghent, Belgium.

    • Jelle van den Ameele
  3. Université Libre de Bruxelles, Laboratory of Neurophysiology and ULB Neuroscience Institute, Belgium.

    • David Gall
  4. University of Minnesota, Lillehei Heart Institute, Minneapolis, Minnesota, USA.

    • Michelina Iacovino
    •  & Michael Kyba
  5. Welbio, Université Libre de Bruxelles, Brussels, Belgium.

    • Pierre Vanderhaeghen

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Contributions

L.T., J.v.d.A., J.D., J.P., D.G., A.H., A.B. and J.B. performed all experiments. T.B., M.I. and M.K. provided crucial cell reagents. L.T., J.v.d.A. and P.V. designed and analyzed all experiments and wrote the manuscript.

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The authors declare no competing financial interests.

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Correspondence to Pierre Vanderhaeghen.

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DOI

https://doi.org/10.1038/nn.3264

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