Transcriptional and epigenetic dysregulation impairs generation of proliferative neural stem and progenitor cells during brain aging

Here we show that the aging of neural stem and progenitor cells (NSPCs) in the mouse brain is characterized by a decrease in the generation efficacy of proliferative NSPCs, rather than the changes in lineage specificity of NSPCs. We reveal that the downregulation of age-dependent genes in NSPCs drives cell aging by decreasing the population of actively proliferating NSPCs, while increasing the expression of quiescence markers. We find that epigenetic deregulation of MLL complex at promoters leads to transcriptional inactivation of age-dependent genes, highlighting the importance of the dynamic interaction between histone modifiers and gene regulatory elements in regulating transcriptional program of aging cells. Our study sheds light on the key intrinsic mechanisms driving stem cell aging through epigenetic regulators and identifies potential rejuvenation targets that could restore the function of aging stem cells. Single-cell RNA-seq, bulk RNA-seq, ChIP-seq, and ATAC-seq were conducted to investigate the transcriptional and epigenetic mechanisms underlying the aging of neural stem and progenitor cells. ChIP-seq was carried out on both young and aged cells to profile key histone marks, including H3K4me3, H3K27me3, and H3K27ac, as well as the MLL complex.