Paul Flicek, Dirk Dolle, Diogo S. Castro, Alexandre A.S.F. Raposo, Francisca F. Vasconcelos, Angela Bithell, Laurence Ettwiller, Sébastien Gillotin, Carlos Parras, Gregory E. Crawford, Debbie L. C. van den Berg, Corentine Marie, François Guillemot, Daniela Drechsel, Noel J. Buckley, Benedikt Berninger, Caroline Johnston, Instituto Gulbenkian de Ciência [Oeiras] (IGC), Fundação Calouste Gulbenkian, MRC National Institute for Medical Research, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre for the Cellular Basis of Behavior, European Molecular Biology Laboratory, European Bioinformatics Institute, The Wellcome Trust Sanger Institute [Cambridge], University of Reading (UOR), Centre for Organismal Studies EMBL (COS), Universität Heidelberg [Heidelberg], Duke University [Durham], Surgical Department of the LMU Munich, Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University Mainz-Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Department of Psychiatry [Oxford] (POWIC), University of Oxford-The Warneford Hospital, HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Medical Center of the Johannes Gutenberg-University Mainz-Johannes Gutenberg - Universität Mainz (JGU), University of Oxford [Oxford]-The Warneford Hospital, Universität Heidelberg [Heidelberg] = Heidelberg University, and Raposo, A
Summary The proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how Ascl1 interacts with the chromatin landscape to regulate gene expression when promoting neuronal differentiation. We find that Ascl1 binding occurs mostly at distal enhancers and is associated with activation of gene transcription. Surprisingly, the accessibility of Ascl1 to its binding sites in neural stem/progenitor cells remains largely unchanged throughout their differentiation, as Ascl1 targets regions of both readily accessible and closed chromatin in proliferating cells. Moreover, binding of Ascl1 often precedes an increase in chromatin accessibility and the appearance of new regions of open chromatin, associated with de novo gene expression during differentiation. Our results reveal a function of Ascl1 in promoting chromatin accessibility during neurogenesis, linking the chromatin landscape at Ascl1 target regions with the temporal progression of its transcriptional program., Graphical Abstract, Highlights • Genome-wide binding of Ascl1 correlates with transcription activation • Ascl1 can bind to both open and closed chromatin in proliferating cells • Ascl1 promotes local chromatin accessibility at its target sites • Chromatin dynamics at Ascl1 sites regulates temporal progression of its program, The proneural transcription factor Ascl1 sequentially activates target genes in proliferating and differentiating progenitors during neurogenesis. Here Raposo et al. show that Ascl1 binds closed and open chromatin in proliferating cells. Binding to closed chromatin promotes accessibility and activation of differentiation specific genes. Thus, dynamics of chromatin landscape at Ascl1 target regions regulate the temporal onset of Ascl1 targets.