Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis
Alexandre A.S.F. Raposo,
Francisca F. Vasconcelos,
Daniela Drechsel,
Corentine Marie,
Caroline Johnston,
Dirk Dolle,
Angela Bithell,
Sébastien Gillotin,
Debbie L.C. van den Berg,
Laurence Ettwiller,
Paul Flicek,
Gregory E. Crawford,
Carlos M. Parras,
Benedikt Berninger,
Noel J. Buckley,
François Guillemot,
Diogo S. Castro
Affiliations
Alexandre A.S.F. Raposo
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
Francisca F. Vasconcelos
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
Daniela Drechsel
MRC National Institute for Medical Research, London NW7 1AA, UK
Corentine Marie
Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR-S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, 75013 Paris, France
Caroline Johnston
Centre for the Cellular Basis of Behavior, Institute of Psychiatry, King’s College London, London SE5 9NU, UK
Dirk Dolle
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
Angela Bithell
University of Reading, School of Pharmacy, Hopkins Life Sciences Building, Reading RG6 6AP, UK
Sébastien Gillotin
MRC National Institute for Medical Research, London NW7 1AA, UK
Debbie L.C. van den Berg
MRC National Institute for Medical Research, London NW7 1AA, UK
Laurence Ettwiller
Centre for Organismal Studies (COS), Ruprecht-Karls-University, 69120 Heidelberg, Germany
Paul Flicek
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
Gregory E. Crawford
Institute of Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
Carlos M. Parras
Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR-S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, 75013 Paris, France
Benedikt Berninger
Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Noel J. Buckley
Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
François Guillemot
MRC National Institute for Medical Research, London NW7 1AA, UK
Diogo S. Castro
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
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.
