Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline.

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Lupo, Giuseppe 
Nisi, Paola S 
Esteve, Pilar 
Paul, Yu-Lee 
Novo, Clara Lopes 

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.

DNA methylation, epigenetics, histone methylation, neural stem/progenitor cells, neurospheres, subventricular zone, Aging, Animals, Cell Proliferation, Cells, Cultured, Homeodomain Proteins, Neural Stem Cells, Neurogenesis
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Aging Cell
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Medical Research Council (MC_PC_12009)
This work was supported by grants to P.J.R.-G. from the 6 Wellcome Trust (WT093736) and the BBSRC (BB/P013406/1, BB/M022285/1), by funding from 7 Sapienza University of Rome (G.L, S.B., E.C) and by a grant from the Spanish Ministry of 8 Economy to P.B. (BFU2016-75412-R, co-financed by FEDER). The Babraham Institute Biological 9 Services Unit is supported by Campus Capability Grant funding from the BBSRC.