title: Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal.
abstract: The gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self-renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self-renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence.
authors.affiliation: Centre for Organismal Studies (COS) Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany; benmartynoga@gmail.com juan.mateo@cos.uni-heidelberg.de.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Mateo
authors.affiliation: Division of Molecular Neurobiology, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom;
authors.forename: Debbie L C
authors.initials: DL
authors.lastname: van den Berg
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom;
authors.forename: Maximilian
authors.initials: M
authors.lastname: Haeussler
authors.affiliation: Division of Molecular Neurobiology, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom;
authors.forename: Daniela
authors.initials: D
authors.lastname: Drechsel
authors.affiliation: Division of Molecular Neurobiology, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom;
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Gaber
authors.affiliation: Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal;
authors.forename: Diogo S
authors.initials: DS
authors.lastname: Castro
authors.affiliation: Developmental Cellomics Laboratory, Genome Institute of Singapore, Singapore 138672, Singapore;
authors.forename: Paul
authors.initials: P
authors.lastname: Robson
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
authors.affiliation: Institute of Genome Sciences and Policy, Duke University, Durham, North Carolina 27708, USA;
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom;
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Centre for Organismal Studies (COS) Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany; New England Biolabs, Inc., Ipswich, Massachusetts 01938-2723, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ettwiller
authors.affiliation: Centre for Organismal Studies (COS) Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Wittbrodt
authors.affiliation: Division of Molecular Neurobiology, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom;
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
authors.affiliation: Division of Molecular Neurobiology, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom; benmartynoga@gmail.com juan.mateo@cos.uni-heidelberg.de.
authors.forename: Ben
authors.initials: B
authors.lastname: Martynoga
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016000:Cluster Analysis; D057890:Epigenomics; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D016015:Logistic Models; D051379:Mice; D046228:Microarray Analysis; D008962:Models, Theoretical; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology*; D000076104:Oligodendrocyte Transcription Factor 2; D012045:Regulatory Sequences, Nucleic Acid; D055747:SOX Transcription Factors / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051839:NFI Transcription Factors; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D055747:SOX Transcription Factors; C512773:Olig2 protein, mouse