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

Nature Neuroscience volume 15, pages 1627–1635 (2012)Cite this article

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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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Figure 1: BCL6 triggers neuronal differentiation during ESC-derived cortical neurogenesis.
Figure 2: BCL6 induces precocious neuronal differentiation during in vivo corticogenesis.
Figure 3: BCL6 is required for proper corticogenesis in vivo.
Figure 4: BCL6 is required for cortical neurogenesis in vivo.
Figure 5: BCL6 induces neurogenesis through repression of Hes5.
Figure 6: BCL6 directly represses the transcription of the Notch target Hes5.
Figure 7: BCL6 inhibits Maml1 recruitment at the Hes5 promoter.
Figure 8: BCL6 neurogenic effect requires Sirt1 recruitment at the Hes5 promoter to modulate histone acetylation.

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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.

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  1. Luca Tiberi and Jelle van den Ameele: These authors contributed equally to this work.

Authors and 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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Correspondence to Pierre Vanderhaeghen.

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Tiberi, L., van den Ameele, J., Dimidschstein, J. et al. BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets. Nat Neurosci 15, 1627–1635 (2012). https://doi.org/10.1038/nn.3264

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