Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence

  1. François Guillemot1,6
  1. 1Division of Molecular Neurobiology, MRC-National Institute for Medical Research, London NW7 1AA, United Kingdom;
  2. 2Centre for Organismal Studies (COS) Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany;
  3. 3Department of Biochemistry, Developmental Genomics Group, Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York, 14203, USA;
  4. 4Research Department of Cancer Biology, University College London, Cancer Institute, London WC1E 6BT, United Kingdom;
  5. 5The School of Biomedical Sciences, The Queensland Brain Institute, The University of Queensland, Brisbane, Australia

    Abstract

    The majority of neural stem cells (NSCs) in the adult brain are quiescent, and this fraction increases with aging. Although signaling pathways that promote NSC quiescence have been identified, the transcriptional mechanisms involved are mostly unknown, largely due to lack of a cell culture model. In this study, we first demonstrate that NSC cultures (NS cells) exposed to BMP4 acquire cellular and transcriptional characteristics of quiescent cells. We then use epigenomic profiling to identify enhancers associated with the quiescent NS cell state. Motif enrichment analysis of these enhancers predicts a major role for the nuclear factor one (NFI) family in the gene regulatory network controlling NS cell quiescence. Interestingly, we found that the family member NFIX is robustly induced when NS cells enter quiescence. Using genome-wide location analysis and overexpression and silencing experiments, we demonstrate that NFIX has a major role in the induction of quiescence in cultured NSCs. Transcript profiling of NS cells overexpressing or silenced for Nfix and the phenotypic analysis of the hippocampus of Nfix mutant mice suggest that NFIX controls the quiescent state by regulating the interactions of NSCs with their microenvironment.

    Keywords

    Footnotes

    • Received March 1, 2013.
    • Accepted July 24, 2013.

    This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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