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

Publication date: Available online 22 June 2017
Source:Cell Stem Cell
Author(s): Unmesh Jadhav, Madhurima Saxena, Nicholas K. O'Neill, Assieh Saadatpour, Guo-Cheng Yuan, Zachary Herbert, Kazutaka Murata, Ramesh A. Shivdasani
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 Bmi1^GFP 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 Bmi1^GFP+ cells, these findings reveal how chromatin status underlies intestinal cell diversity and dedifferentiation to restore ISC function and intestinal homeostasis.

Graphical abstract

Teaser

Jadhav et al. identify an active enhancer signature that distinguishes Lgr5⁺ intestinal stem cells (ISCs) from Bmi1^GFP+ 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.


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