Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multi-functional regulator of self-renewal
- Juan L. Mateo1,
- Debbie L.C. van den Berg2,
- Maximilian Haeussler3,
- Daniela Drechsel2,
- Zachary B. Gaber2,
- Diogo S. Castro4,
- Paul Robson5,
- Gregory E. Crawford6,
- Paul Flicek7,
- Laurence Ettwiller8,
- Joachim Wittbrodt1,
- François Guillemot2 and
- Ben Martynoga2,9
- 1 University of Heidelberg;
- 2 National Institute for Medical Research;
- 3 University of Manchester, University of California Santa Cruz;
- 4 Instituto Gulbenkian de Ciência;
- 5 Genome Institute of Singapore;
- 6 Duke University;
- 7 European Bioinformatics Institute, Wellcome Trust Sanger Institute;
- 8 University of Heidelberg, New England Biolabs
- ↵* Corresponding author; email: benmartynoga{at}gmail.com
Abstract
The gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterised. Knowledge of the central transcription factors (TFs), the non-coding 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.
- Received January 31, 2014.
- Accepted September 29, 2014.
- Published by Cold Spring Harbor Laboratory Press
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