BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets
Tiberi, Luca van den Ameele, Jelle Dimidschstein, Jordane Piccirilli, Julie Gall, David Herpoel, Adèle Bilheu, Angéline Bonnefont, Jerome Iacovino, Michelina Kyba, Michael Bouschet, Tristan Vanderhaeghen, Pierre # ×
Nature America Inc.
Nature Neuroscience vol:15 issue:12
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.