E-MTAB-2350 - DNA methylation is required for the control of stem cell differentiation in the small intestine
Released on 13 March 2014, last updated on 3 May 2014
The mammalian intestinal epithelium has a unique organization where crypts harboring stem cells produce progenitors and finally clonal populations of differentiated cells. Remarkably, the epithelium is replaced every three to five days throughout adult life. Disrupted maintenance of the intricate balance of proliferation and differentiation leads to loss of epithelial integrity, barrier function, or cancer. There is a tight correlation between 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 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.
methylation profiling by high throughput sequencing, ChIP-seq, RNA-seq of coding RNA, binding site identification design, cell type comparison design, co-expression, in vivo, reference design
DNA methylation is required for the control of stem cell differentiation in the small intestine. Karyn L. Sheaffer, Rinho Kim, Reina Aoki, Ellen N. Elliott, Jonathan Schug, Lukas Burger, Dirk Schubeler, Klaus H. Kaestner.