Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence
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Ben Martynoga Juan L Mateo Bo Zhou Jimena Andersen Angeliki Achimastou Noelia Urbán Debbie van den Berg Dimitra Georgopoulou Suzana Hadjur Joachim Wittbrodt Laurence Ettwiller Michael Piper Richard M Gronostajski Francois GuillemotAbstract
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.
Journal details
Journal Genes & Development
Volume 27
Issue number 16
Pages 1769-1786
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Publisher website (DOI) 10.1101/gad.216804.113
Europe PubMed Central 23964093
Pubmed 23964093
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