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

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


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.

Publication types

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

MeSH terms

  • Animals
  • Cell Dedifferentiation*
  • Duodenum / cytology
  • Duodenum / metabolism*
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / metabolism*
  • Mice
  • Mice, Transgenic
  • Receptors, G-Protein-Coupled*
  • Stem Cells / cytology
  • Stem Cells / metabolism*


  • Lgr5 protein, mouse
  • Receptors, G-Protein-Coupled