Abstract
SummaryAdult neurogenesis declines with aging due to the depletion and functional impairment of neural stem/progenitor cells (NSPCs). An improved understanding of the underlying mechanisms that drive age‐associated neurogenic deficiency could lead to the development of strategies to alleviate cognitive impairment and facilitate neuroregeneration. An essential step towards this aim is to investigate the molecular changes that occur in NSPC aging on a genomewide scale. In this study, we compare the transcriptional, histone methylation and DNA methylation signatures of NSPCs derived from the subventricular zone (SVZ) of young adult (3 months old) and aged (18 months old) mice. Surprisingly, the transcriptional and epigenomic profiles of SVZ‐derived NSPCs are largely unchanged in aged cells. Despite the global similarities, we detect robust age‐dependent changes at several hundred genes and regulatory elements, thereby identifying putative regulators of neurogenic decline. Within this list, the homeobox gene Dbx2 is upregulated in vitro and in vivo, and its promoter region has altered histone and DNA methylation levels, in aged NSPCs. Using functional in vitro assays, we show that elevated Dbx2 expression in young adult NSPCs promotes age‐related phenotypes, including the reduced proliferation of NSPC cultures and the altered transcript levels of age‐associated regulators of NSPC proliferation and differentiation. Depleting Dbx2 in aged NSPCs caused the reverse gene expression changes. Taken together, these results provide new insights into the molecular programmes that are affected during mouse NSPC aging, and uncover a new functional role for Dbx2 in promoting age‐related neurogenic decline.
Highlights
In the adult mouse forebrain, neurogenesis persists in two restricted niches located in the subventricular zone (SVZ) close to the lateral ventricles and in the subgranular zone (SGZ) within the dentate gyrus
Aging is associated with reduced neurogenesis in the mouse SVZ and SGZ (Encinas et al, 2011; Enwere et al, 2004; Lugert et al, 2010; Luo, Daniels, Lennington, Notti & Conover, 2006), which might lead to decreased olfactory function and cognitive hippocampus-dependent impairment (Goncalves et al, 2016; Lledo & Valley, 2016)
We identified 30,406 H3K4me3 peaks (MACS, p < 1EÀ9) that were associated with 13,030 transcriptional start sites (TSS) in adult neural stem/progenitor cells (NSPCs), and 28,854 peaks associated with 12,955 TSS in aged NSPCs
Summary
In the adult mouse forebrain, neurogenesis persists in two restricted niches located in the subventricular zone (SVZ) close to the lateral ventricles and in the subgranular zone (SGZ) within the dentate gyrus. Aging is associated with reduced neurogenesis in the mouse SVZ and SGZ (Encinas et al, 2011; Enwere et al, 2004; Lugert et al, 2010; Luo, Daniels, Lennington, Notti & Conover, 2006), which might lead to decreased olfactory function and cognitive hippocampus-dependent impairment (Goncalves et al, 2016; Lledo & Valley, 2016) This age-associated neurogenic decline appears to be caused both by a depletion in the NSPC pool of the aged niche (Ahlenius, Visan, Kokaia, Lindvall & Kokaia, 2009; Bouab, Paliouras, Aumont, Forest-Berard & Fernandes, 2011; Corenblum et al, 2016; Enwere et al, 2004; Luo et al, 2006; Maslov, Barone, Plunkett & Pruitt, 2004; Molofsky et al, 2006; Stoll et al, 2011) and by the decreased capacity of the remaining NSPCs to sustain proliferation and neuronal differentiation, as revealed by in vitro studies (Ahlenius et al, 2009; Apostolopoulou et al, 2017; Corenblum et al, 2016; Daynac, Morizur, Chicheportiche, Mouthon & Boussin, 2016; Daynac et al, 2014; L’Episcopo et al, 2013; Shi et al, 2017; Zhu et al, 2014). Example genes include: Adap, Cldn, Hex, Msrb, Nrg e 119 CpG DMR lower 211 CpG DMR higher 5mC in aged vs adult 5mC in aged vs adult
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