Journal
CELL REPORTS
Volume 8, Issue 5, Pages 1290-1299Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.07.060
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Funding
- VA [1I01 BX000252-01]
- NIH [DP2-OD006505-01]
- Sontag Foundation
- Italian Ministry of Health
- Italian Association for Cancer Research
- Grants-in-Aid for Scientific Research [26712026] Funding Source: KAKEN
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The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here, we show that JMJD3, a histone H3 lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life.
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