Cell and chromatin transitions in intestinal stem cell regeneration
Open Access
- 23 June 2022
- journal article
- research article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 36 (11-12), 684-698
- https://doi.org/10.1101/gad.349412.122
Abstract
The progeny of intestinal stem cells (ISCs) dedifferentiate in response to ISC attrition. The precise cell sources, transitional states, and chromatin remodeling behind this activity remain unclear. In the skin, stem cell recovery after injury preserves an epigenetic memory of the damage response; whether similar memories arise and persist in regenerated ISCs is not known. We addressed these questions by examining gene activity and open chromatin at the resolution of single Neurog3-labeled mouse intestinal crypt cells, hence deconstructing forward and reverse differentiation of the intestinal secretory (Sec) lineage. We show that goblet, Paneth, and enteroendocrine cells arise by multilineage priming in common precursors, followed by selective access at thousands of cell-restricted cis-elements. Selective ablation of the ISC compartment elicits speedy reversal of chromatin and transcriptional features in large fractions of precursor and mature crypt Sec cells without obligate cell cycle re-entry. ISC programs decay and reappear along a cellular continuum lacking discernible discrete interim states. In the absence of gross tissue damage, Sec cells simply reverse their forward trajectories, without invoking developmental or other extrinsic programs, and starting chromatin identities are effectively erased. These findings identify strikingly plastic molecular frameworks in assembly and regeneration of a self-renewing tissue.Keywords
Funding Information
- National Institutes of Health (R01DK081113, R01DK082889)
- Lind
- Neuroendocrine Tumor Research Foundation
This publication has 60 references indexed in Scilit:
- Notch signaling differentially regulates the cell fate of early endocrine precursor cells and their maturing descendants in the mouse pancreas and intestineDevelopmental Biology, 2012
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populationsProceedings of the National Academy of Sciences of the United States of America, 2011
- Intestinal Stem Cell Replacement Follows a Pattern of Neutral DriftScience, 2010
- Intestinal Crypt Homeostasis Results from Neutral Competition between Symmetrically Dividing Lgr5 Stem CellsCell, 2010
- Cell Lineage metastability in Gfi1-deficient mouse intestinal epitheliumDevelopmental Biology, 2010
- Finding distal regulatory elements in the human genomeCurrent Opinion in Genetics & Development, 2009
- A robust and high-throughput Cre reporting and characterization system for the whole mouse brainNature Neuroscience, 2009
- Identification of stem cells in small intestine and colon by marker gene Lgr5Nature, 2007
- Neurogenin 3-expressing progenitor cells in the gastrointestinal tract differentiate into both endocrine and non-endocrine cell typesDevelopmental Biology, 2004