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

Vionnie W C Yu; Rushdia Z Yusuf; Toshihiko Oki; Juwell Wu; Borja Saez; Xin Wang; Colleen Cook; Ninib Baryawno; Michael J Ziller; Eunjung Lee; Hongcang Gu; Alexander Meissner; Charles P Lin; Peter V Kharchenko; David T Scadden

doi:10.1016/j.cell.2016.10.045

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

Cell. 2016 Nov 17;167(5):1310-1322.e17. doi: 10.1016/j.cell.2016.10.045.

Authors

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
² Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
³ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
⁴ Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
⁵ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁶ Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
⁸ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: [email protected].

PMID: 27863245
DOI: 10.1016/j.cell.2016.10.045

Abstract

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Lineage
Clone Cells / cytology
Epigenomics*
Fluorescence
Hematopoiesis
Hematopoietic Stem Cells / cytology*
Inflammation / pathology
Mice
Transcription, Genetic

Abstract

Publication types

MeSH terms

Grants and funding