DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus

Lucas T.J. Kaaij, Marc van de Wetering, Fang Fang, Benjamin Decato, Antoine Molaro, Harmen J.G. van de Werken, Johan H. van Es, Jurian Schuijers, Elzo de Wit, Wouter de Laat, Gregory J. Hannon, Hans C. Clevers, Andrew D. Smith, René F. Ketting*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

90 Citations (Scopus)


Background: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Article numberR50
JournalGenome Biology
Issue number5
Publication statusPublished - 28 May 2013

Bibliographical note

Funding Information:
We acknowledge members of the Ketting, Clevers, and Smith labs for helpful discussions and technical assistance. Members of the Cuppen group are thanked for their computational help. This work was supported by an ERC Starting Grant (RFK) from the Ideas Program of the European Union Seventh Framework Program (202819) and the US National Institutes of Health National Human Genome Research Institute grant R01 HG005238 (ADS).


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