title: DNA methylation is required for the control of stem cell differentiation in the small intestine.
abstract: 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.
authors.affiliation: Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Karyn L
authors.initials: KL
authors.lastname: Sheaffer
authors.forename: Rinho
authors.initials: R
authors.lastname: Kim
authors.forename: Reina
authors.initials: R
authors.lastname: Aoki
authors.forename: Ellen N
authors.initials: EN
authors.lastname: Elliott
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schug
authors.forename: Lukas
authors.initials: L
authors.lastname: Burger
authors.forename: Dirk
authors.initials: D
authors.lastname: Schübeler
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007421:Intestine, Small / Q000166:cytology*; D051379:Mice; D013234:Stem Cells / Q000166:cytology*
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse
keywords: DNA methylation; Dnmt1; intestinal stem cell