Cell
Volume 167, Issue 5, 17 November 2016, Pages 1310-1322.e17
Journal home page for Cell

Article
Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells

https://doi.org/10.1016/j.cell.2016.10.045Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Clonal tracking demonstrates clone-specific functional heterogeneity in vivo

  • Stereotypical functions of HSCs are preserved under stress or tissue injury

  • HSC clonal behavior is associated with a distinct epigenetic pattern

  • HSC is epigenetically constrained with limited plasticity in response to cues

Summary

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 over time 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 is warranted.

Keywords

clonal tracking
hematopoietic stem cell
hematopoiesis
multi-fluorescent mouse model
epigenetic memory
lineage tracing
RNA-seq
single cell
ATAC-seq
transplantation

Cited by (0)

8

Lead Contact