show Abstracthide AbstractHematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Here, we performed an integrated analysis of transcriptome and chromatin accessibility of aged HSCs and downstream progenitors. Alterations in chromatin accessibility preferentially took place in HSCs with aging, which gradually resolved with differentiation. Differentially open accessible regions (open DARs) in aged HSCs showed enrichment of binding motifs of the STAT, ATF, and CNC family transcription factors that are activated in response to external stresses, and most of them comprised active, primed , and inactive enhancers. Genes linked to open DARs showed significantly higher levels of basal expression and their expression reached significantly higher peaks after cytokine stimulation in aged HSCs than in young HSCs, suggesting that open DARs contribute to augmented transcriptional responses under stress conditions. These results indicate that the ongoing and/or history of exposure to external stresses is epigenetically inscribed in HSCs to augment their responses to external stimuli. Overall design: RNA-seq of Young and Aged hematopoietic cells