Open AccessMolecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline
Author(s) -
Lupo Giuseppe,
Nisi Paola S.,
Esteve Pilar,
Paul YuLee,
Novo Clara Lopes,
Sidders Ben,
Khan Muhammad A.,
Biagioni Stefano,
Liu HaiKun,
Bovolenta Paola,
Cacci Emanuele,
RuggGunn Peter J.
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12745
Subject(s) - biology , dna methylation , neurogenesis , progenitor cell , histone , epigenetics , subventricular zone , neural stem cell , epigenomics , progenitor , genetics , stem cell , gene expression , gene
Summary Adult neurogenesis declines with aging due to the depletion and functional impairment of neural stem/progenitor cells ( NSPC s). 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 NSPC s 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 NSPC s 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 NSPC s. Using functional in vitro assays, we show that elevated Dbx2 expression in young adult NSPC s 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 NSPC s 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.