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

Index: 10.1016/j.stem.2017.05.001

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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 fromBmi1GFPmice 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 ofciselements 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.