Imprinting epigenetic memories in chromatin accessibility in hematopoietic stem cells with aging (RNA-seq cytokine stimulation)

Hematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Epigenetic alterations are one of the hallmarks of HSC aging, and profiling of DNA and histone modifications has provided potential mechanisms underlying HSC aging. Here, we performed an integrated analysis of transcriptome and chromatin accessibility of aged HSCs. Alterations in chromatin accessibility preferentially took place in HSCs with aging, the cells at the top of the hematopoietic hierarchy, suggesting that the epigenetic memories are imprinted in HSCs and are inherited by downstream progenitors. However, most genes with differentially accessible regions (DARs) were not actively transcribed and kept being poised for activation in aged HSCs. Motifs of ATF, STAT, and CNC family transcription factors were significantly enriched at DARs in aged HSCs. These transcription factors are activated in response to external stresses, such as cytokines and inflammation signals, and oxidative stresses. Enrichment of these motifs in aged HSCs implicates the history of exposure to such stresses and suggests that recurrent exposure to stress signals changes chromatin accessibility to augment the responses of trained HSCs to subsequent stimuli. Conversely, aged HSC-specific gene expression occurred mostly at gene loci with poised accessible regions, but not at DARs, without accompanying drastic chromatin reorganization, suggesting that altered external signals from the aged niche largely account for this process. Our findings provide key epigenetic insights into HSC aging and serve as a reference for future studies.