Kaaij Lucas T J, van de Wetering Marc, Fang Fang, Decato Benjamin, Molaro Antoine, van de Werken Harmen J G, van Es Johan H, Schuijers Jurian, de Wit Elzo, de Laat Wouter, Hannon Gregory J, Clevers Hans C, Smith Andrew D, Ketting René F
Genome Biol. 2013 May 28;14(5):R50. doi: 10.1186/gb-2013-14-5-r50.
DNA methylation is of pivotal importance during development. Previous genome-wide studies identified numerous differentially methylated regions upon differentiation of stem cells, many of them associated with transcriptional start sites.
We present the first genome-wide, single-base-resolution view into DNA methylation dynamics during differentiation of a mammalian epithelial stem cell: the mouse small intestinal Lgr5+ stem cell. Very little change was observed at transcriptional start sites and our data suggest that differentiation-related genes are already primed for expression in the stem cell. Genome-wide, only 50 differentially methylated regions were identified. Almost all of these loci represent enhancers driving gene expression in the differentiated part of the small intestine. Finally, we show that binding of the transcription factor Tcf4 correlates with hypo-methylation and demonstrate that Tcf4 is one of the factors contributing to formation of differentially methylated regions.
Our results reveal limited DNA methylation dynamics during small intestine stem cell differentiation and an impact of transcription factor binding on shaping the DNA methylation landscape during differentiation of stem cells in vivo.
DNA甲基化在发育过程中至关重要。先前的全基因组研究在干细胞分化过程中鉴定出许多差异甲基化区域，其中许多与转录起始位点相关。
我们展示了首个关于哺乳动物上皮干细胞（小鼠小肠Lgr5 +干细胞）分化过程中DNA甲基化动态变化的全基因组、单碱基分辨率视图。在转录起始位点观察到的变化非常小，我们的数据表明，与分化相关的基因在干细胞中已经做好了表达的准备。在全基因组范围内，仅鉴定出50个差异甲基化区域。几乎所有这些位点都代表着驱动小肠分化部分基因表达的增强子。最后，我们表明转录因子Tcf4的结合与低甲基化相关，并证明Tcf4是促成差异甲基化区域形成的因素之一。
我们的结果揭示了小肠干细胞分化过程中有限的DNA甲基化动态变化，以及转录因子结合对体内干细胞分化过程中DNA甲基化格局形成的影响。
