title: Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence.
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.
authors: Division of Molecular Neurobiology, MRC-National Institute for Medical Research, London NW7 1AA, United Kingdom.
authors: Ben
authors: B
authors: Martynoga
authors: Juan L
authors: JL
authors: Mateo
authors: Bo
authors: B
authors: Zhou
authors: Jimena
authors: J
authors: Andersen
authors: Angeliki
authors: A
authors: Achimastou
authors: Noelia
authors: N
authors: Urbán
authors: Debbie
authors: D
authors: van den Berg
authors: Dimitra
authors: D
authors: Georgopoulou
authors: Suzana
authors: S
authors: Hadjur
authors: Joachim
authors: J
authors: Wittbrodt
authors: Laurence
authors: L
authors: Ettwiller
authors: Michael
authors: M
authors: Piper
authors: Richard M
authors: RM
authors: Gronostajski
authors: François
authors: F
authors: Guillemot
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D051839:NFI Transcription Factors; C497650:Nfix protein, mouse
keywords: NFIX; epigenetics; genomics; neural stem cells; nuclear factor one; quiescence; transcription factor
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