Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
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Σάββατο 24 Ιουνίου 2017

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 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.

Graphical abstract

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Teaser

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.


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