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


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.

SUBMITTER: Jadhav U 

PROVIDER: S-EPMC5505276 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Jadhav Unmesh U   Saxena Madhurima M   O'Neill Nicholas K NK   Saadatpour Assieh A   Yuan Guo-Cheng GC   Herbert Zachary Z   Murata Kazutaka K   Shivdasani Ramesh A RA  

Cell stem cell 20170622 1


Replicating Lgr5<sup>+</sup> stem cells and quiescent Bmi1<sup>+</sup> cells behave as intestinal stem cells (ISCs) in vivo. Disrupting Lgr5<sup>+</sup> ISCs triggers epithelial renewal from Bmi1<sup>+</sup> 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<sup>+</sup> cells from Bmi1<sup>GFP</sup> mice are preterminal enteroendocrine cells and we identify CD69<sup>+</sup>CD274<  ...[more]

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