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DNA methylation is required for the control of stem cell differentiation in the small intestine
The mammalian intestinal epithelium has a unique organization in which crypts harboring stem cells produce progenitors and finally clonal populations of differentiated cells. Remarkably, the epithelium is replaced every 3–5 d throughout adult life. Disrupted maintenance of the intricate balance of p...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967052/ https://www.ncbi.nlm.nih.gov/pubmed/24637118 http://dx.doi.org/10.1101/gad.230318.113 |
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author | Sheaffer, Karyn L. Kim, Rinho Aoki, Reina Elliott, Ellen N. Schug, Jonathan Burger, Lukas Schübeler, Dirk Kaestner, Klaus H. |
author_facet | Sheaffer, Karyn L. Kim, Rinho Aoki, Reina Elliott, Ellen N. Schug, Jonathan Burger, Lukas Schübeler, Dirk Kaestner, Klaus H. |
author_sort | Sheaffer, Karyn L. |
collection | PubMed |
description | The mammalian intestinal epithelium has a unique organization in which crypts harboring stem cells produce progenitors and finally clonal populations of differentiated cells. Remarkably, the epithelium is replaced every 3–5 d throughout adult life. Disrupted maintenance of the intricate balance of proliferation and differentiation leads to loss of epithelial integrity or barrier function or to cancer. There is a tight correlation between the epigenetic status of genes and expression changes during differentiation; however, the mechanism of how changes in DNA methylation direct gene expression and the progression from stem cells to their differentiated descendants is unclear. Using conditional gene ablation of the maintenance methyltransferase Dnmt1, we demonstrate that reducing DNA methylation causes intestinal crypt expansion in vivo. Determination of the base-resolution DNA methylome in intestinal stem cells and their differentiated descendants shows that DNA methylation is dynamic at enhancers, which are often associated with genes important for both stem cell maintenance and differentiation. We establish that the loss of DNA methylation at intestinal stem cell gene enhancers causes inappropriate gene expression and delayed differentiation. |
format | Online Article Text |
id | pubmed-3967052 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-39670522014-09-15 DNA methylation is required for the control of stem cell differentiation in the small intestine Sheaffer, Karyn L. Kim, Rinho Aoki, Reina Elliott, Ellen N. Schug, Jonathan Burger, Lukas Schübeler, Dirk Kaestner, Klaus H. Genes Dev Resource/Methodology The mammalian intestinal epithelium has a unique organization in which crypts harboring stem cells produce progenitors and finally clonal populations of differentiated cells. Remarkably, the epithelium is replaced every 3–5 d throughout adult life. Disrupted maintenance of the intricate balance of proliferation and differentiation leads to loss of epithelial integrity or barrier function or to cancer. There is a tight correlation between the epigenetic status of genes and expression changes during differentiation; however, the mechanism of how changes in DNA methylation direct gene expression and the progression from stem cells to their differentiated descendants is unclear. Using conditional gene ablation of the maintenance methyltransferase Dnmt1, we demonstrate that reducing DNA methylation causes intestinal crypt expansion in vivo. Determination of the base-resolution DNA methylome in intestinal stem cells and their differentiated descendants shows that DNA methylation is dynamic at enhancers, which are often associated with genes important for both stem cell maintenance and differentiation. We establish that the loss of DNA methylation at intestinal stem cell gene enhancers causes inappropriate gene expression and delayed differentiation. Cold Spring Harbor Laboratory Press 2014-03-15 /pmc/articles/PMC3967052/ /pubmed/24637118 http://dx.doi.org/10.1101/gad.230318.113 Text en © 2014 Sheaffer et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Resource/Methodology Sheaffer, Karyn L. Kim, Rinho Aoki, Reina Elliott, Ellen N. Schug, Jonathan Burger, Lukas Schübeler, Dirk Kaestner, Klaus H. DNA methylation is required for the control of stem cell differentiation in the small intestine |
title | DNA methylation is required for the control of stem cell differentiation in the small intestine |
title_full | DNA methylation is required for the control of stem cell differentiation in the small intestine |
title_fullStr | DNA methylation is required for the control of stem cell differentiation in the small intestine |
title_full_unstemmed | DNA methylation is required for the control of stem cell differentiation in the small intestine |
title_short | DNA methylation is required for the control of stem cell differentiation in the small intestine |
title_sort | dna methylation is required for the control of stem cell differentiation in the small intestine |
topic | Resource/Methodology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967052/ https://www.ncbi.nlm.nih.gov/pubmed/24637118 http://dx.doi.org/10.1101/gad.230318.113 |
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