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Cell Stem Cell. 2017 Jul 6;21(1):65-77.e5. doi: 10.1016/j.stem.2017.05.001. Epub 2017 Jun 22.

Dynamic Reorganization of Chromatin Accessibility Signatures during Dedifferentiation of Secretory Precursors into Lgr5+ Intestinal Stem Cells.

Author information

1
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
2
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard TH Chan School of Public Health, Boston, MA 02215, USA.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard TH Chan School of Public Health, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
5
Molecular Biology Core Facility, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. Electronic address: ramesh_shivdasani@dfci.harvard.edu.

Abstract

Replicating Lgr5+ stem cells and quiescent Bmi1+ cells behave as intestinal stem cells (ISCs) in vivo. Disrupting Lgr5+ ISCs triggers epithelial renewal from Bmi1+ cells, from secretory or absorptive progenitors, and from Paneth cell precursors, revealing a high degree of plasticity within intestinal crypts. Here, we show that GFP+ cells from Bmi1GFP mice are preterminal enteroendocrine cells and we identify CD69+CD274+ cells as related goblet cell precursors. Upon loss of native Lgr5+ ISCs, both populations revert toward an Lgr5+ cell identity. While active histone marks are distributed similarly between Lgr5+ ISCs and progenitors of both major lineages, thousands of cis elements that control expression of lineage-restricted genes are selectively open in secretory cells. This accessibility signature dynamically converts to that of Lgr5+ ISCs during crypt regeneration. Beyond establishing the nature of Bmi1GFP+ cells, these findings reveal how chromatin status underlies intestinal cell diversity and dedifferentiation to restore ISC function and intestinal homeostasis.

KEYWORDS:

accessible chromatin; cell plasticity; chromatin modulation; dedifferentiation; facultative stem cells; intestinal stem cells; reserve stem cells

PMID:
28648363
PMCID:
PMC5505276
DOI:
10.1016/j.stem.2017.05.001
[Indexed for MEDLINE]
Free PMC Article

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