Date Published: March 05, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Giuseppe Lupo, Paola S. Nisi, Pilar Esteve, Yu‐Lee Paul, Clara Lopes Novo, Ben Sidders, Muhammad A. Khan, Stefano Biagioni, Hai‐Kun Liu, Paola Bovolenta, Emanuele Cacci, Peter J. Rugg‐Gunn.
Adult 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.
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. In these regions, neural stem/progenitor cells (NSPCs) are maintained throughout adulthood and give rise to daughter cells that undergo differentiation into neurons and glia. Increasing evidence supports a role for adult neurogenesis in normal brain function and suggests that neurological disorders and neurodegeneration may be caused, at least in part, by reduced neuronal output of adult NSPCs (Goncalves, Schafer & Gage, 2016; Lledo & Valley, 2016).
Mouse SVZ and SGZ are complex niches where neurogenesis persists throughout adult life due to a finely regulated balance among NSPC self‐renewal, expansion and differentiation. During aging, this regulation is progressively altered, and neurogenic output is curtailed. To investigate the intrinsic molecular changes upon NSPC aging, we report here a comprehensive set of transcriptional and epigenetic maps in young adult and aged SVZ NSPCs. We found that the NSPC epigenome was largely unchanged upon aging, which is broadly consistent with prior studies that profiled somatic stem cells from other aged tissues (Beerman et al., 2013; Bocker et al., 2011; Bork et al., 2010; Fernandez et al., 2015; Liu et al., 2013; Sun et al., 2014). In contrast to previous reports, we did not detect an age‐associated broadening of H3K4me3 (as in blood stem cells; Sun et al., 2014) and H3K27me3 (as in muscle satellite stem cells; Liu et al., 2013) domains in NSPCs, nor a global acquisition in DNA methylation levels (as in blood stem cells; Beerman et al., 2013; Sun et al., 2014). It is currently unclear what impact these epigenetic changes might have on the aged stem cells, and whether the differences are due to the varied stem cell properties from each tissue, such as cellular potential or the turnover rate, or perhaps influenced by external signals from their niches.
Sequencing data are available at GEO under accession number GSE101610.
G.L. performed conceptualization, resources, funding acquisition, investigation, methodology, supervision, validation, visualization and writing. P.S.N. performed investigation. P.E. and M.A.K. were involved in investigation and visualization. Y.‐L.P. and C.L.N. performed investigation and methodology. B.S. carried out methodology and formal analysis. S.B. performed conceptualization and funding acquisition. H‐K.L. involved in investigation and supervision. P.B. was involved in visualization, resources and funding acquisition. E.C. performed conceptualization, resources, funding acquisition, investigation, methodology, visualization and writing. P.J.R.‐G. performed conceptualization, resources, formal analysis, funding acquisition, supervision, validation, visualization and writing.