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

Unmesh Jadhav, Madhurima Saxena, Nicholas K. O'Neill, Assieh Saadatpour, Guo Cheng Yuan, Zachary Herbert, Kazutaka Murata, Ramesh A. Shivdasani

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

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. Jadhav et al. identify an active enhancer signature that distinguishes Lgr5+ intestinal stem cells (ISCs) from Bmi1GFP+ and other secretory cells, including CD69+CD274+ goblet cell precursors. These specialized cells dedifferentiate into Lgr5+ ISCs in response to stem cell attrition, which is accompanied by dynamic rearrangements in open chromatin signatures.

Original languageEnglish
Pages (from-to)65-77.e5
JournalCell Stem Cell
Volume21
Issue number1
DOIs
StatePublished - 6 Jul 2017
Externally publishedYes

Keywords

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

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