TY  - JOUR
AU  - Lupo, Giuseppe
AU  - Nisi, Paola S
AU  - Esteve, Pilar
AU  - Paul, Yu-Lee
AU  - Novo, Clara Lopes
AU  - Sidders, Ben
AU  - Khan, Muhammad Amir
AU  - Biagioni, Stefano
AU  - Liu, Hai-Kun
AU  - Bovolenta, Paola
AU  - Cacci, Emanuele
AU  - Rugg-Gunn, Peter J
TI  - Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline.
JO  - Aging cell
VL  - 17
IS  - 3
SN  - 1474-9718
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - DKFZ-2018-00622
SP  - e12745 -
PY  - 2018
N1  - DKFZ-ZMBH-Allianz
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29504228
C2  - pmc:PMC5946077
DO  - DOI:10.1111/acel.12745
UR  - https://inrepo02.dkfz.de/record/134832
ER  -