title: BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets.
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.
authors.affiliation: Université Libre de Bruxelles, Institute for Interdisciplinary Research, ULB Neuroscience Institute, Brussels, Belgium.
authors.forename: Luca
authors.initials: L
authors.lastname: Tiberi
authors.forename: Jelle
authors.initials: J
authors.lastname: van den Ameele
authors.forename: Jordane
authors.initials: J
authors.lastname: Dimidschstein
authors.forename: Julie
authors.initials: J
authors.lastname: Piccirilli
authors.forename: David
authors.initials: D
authors.lastname: Gall
authors.forename: Adèle
authors.initials: A
authors.lastname: Herpoel
authors.forename: Angéline
authors.initials: A
authors.lastname: Bilheu
authors.forename: Jerome
authors.initials: J
authors.lastname: Bonnefont
authors.forename: Michelina
authors.initials: M
authors.lastname: Iacovino
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.forename: Tristan
authors.initials: T
authors.lastname: Bouschet
authors.forename: Pierre
authors.initials: P
authors.lastname: Vanderhaeghen
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000502:physiology; D063185:Epigenetic Repression / Q000235:genetics / Q000502:physiology*; D005260:Female; D020868:Gene Silencing; D018390:Gene Targeting / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D021381:Protein Transport / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D056564:Sirtuin 1 / Q000235:genetics / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D051880:Receptors, Notch; D012097:Repressor Proteins; D056564:Sirtuin 1; C490010:Bcl6 protein, mouse; C489685:Hes5 protein, mouse; C470545:Sirt1 protein, mouse