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 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.