Epigenetic Memory Underlies Cell Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells

Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of and molecular basis for heterogeneity we overlaid functional, transcriptional and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation and genotoxic injury, and associated with distinctive transcriptional, DNA methylation and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche are warranted. LKS SLAM cells associated with different clonal clusters were separated using flow cytometry, and examined using RNA-seq, WGBS, ATAC-seq.