title: Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells.
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.
authors.affiliation: 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.
authors.forename: Vionnie W C
authors.initials: VWC
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Rushdia Z
authors.initials: RZ
authors.lastname: Yusuf
authors.affiliation: 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.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Oki
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
authors.forename: Juwell
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Borja
authors.initials: B
authors.lastname: Saez
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Colleen
authors.initials: C
authors.lastname: Cook
authors.affiliation: 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.
authors.forename: Ninib
authors.initials: N
authors.lastname: Baryawno
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ziller
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
authors.forename: Hongcang
authors.initials: H
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: peter.kharchenko@post.harvard.edu.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Kharchenko
authors.affiliation: 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: david_scadden@harvard.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002999:Clone Cells / Q000166:cytology; D057890:Epigenomics; D005453:Fluorescence; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D007249:Inflammation / Q000473:pathology; D051379:Mice; D014158:Transcription, Genetic
keywords: ATAC-seq; RNA-seq; clonal tracking; epigenetic memory; hematopoiesis; hematopoietic stem cell; lineage tracing; multi-fluorescent mouse model; single cell; transplantation