10779/crick.11559786.v1 Jerome Bonnefont Jerome Bonnefont Luca Tiberi Luca Tiberi Jelle van den Ameele Jelle van den Ameele Delphine Potier Delphine Potier Zachary B Gaber Zachary B Gaber Xionghui Lin Xionghui Lin Angéline Bilheu Angéline Bilheu Adèle Herpoel Adèle Herpoel Fausto D Velez Bravo Fausto D Velez Bravo François Guillemot François Guillemot Stein Aerts Stein Aerts Pierre Vanderhaeghen Pierre Vanderhaeghen Cortical neurogenesis requires Bcl6-mediated transcriptional repression of multiple self-renewal-promoting extrinsic pathways. The Francis Crick Institute 2020 Bcl6 FGF signaling Notch signaling SHH signaling Wnt signaling brain development cyclins neurogenesis stemness transcription Guillemot FC001089 AS-ack Neurology & Neurosurgery 1109 Neurosciences 1702 Cognitive Sciences 1701 Psychology 2020-01-09 16:44:34 Journal contribution https://crick.figshare.com/articles/journal_contribution/Cortical_neurogenesis_requires_Bcl6-mediated_transcriptional_repression_of_multiple_self-renewal-promoting_extrinsic_pathways_/11559786 During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here, we combine whole-genome transcriptional and epigenetic analyses with in vivo functional studies to demonstrate that Bcl6, a transcriptional repressor previously reported to promote cortical neurogenesis, acts as a driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 represses its targets through Sirt1 recruitment followed by histone deacetylation. Our data identify a molecular logic by which a single cell-intrinsic factor represses multiple extrinsic pathways that favor self-renewal, thereby ensuring robustness of neuronal fate transition.