The DNA methylome of ground state mouse embryonic stem cells reflect pre-implantation developmental stages

Habibi , Ehsan

Recent analyses of the DNA methylome of early mouse developmental stages and mouse embryonic stem cells (ESCs) grown in serum revealed a marked discrepancy: cells from preimplantation embryos are hypomethylated, whereas serum ESCs are globally hypermethylated. In the september issue of Cell Stem Cell (online now), researchers from the department of Molecular Biology (Ehsan Habibi, Hendrik Marks, Henk Stunnenberg), in collaboration with the department of Hematology (Leonie Kroeze, Joop Jansen) and several other European groups show that ESCs maintained in defined serum-free conditions supplemented with two kinase inhibitors (2i) are overall hypomethylated, faithfully reflecting embryonic Inner Cell Mass cells.

The use of two kinase inhibitors (2i) enables derivation of mouse embryonic stem cells (ESCs) in the pluripotent ground state. Using whole-genome bisulfite sequencing (WGBS), we show that male 2i ESCs are globally hypomethylated compared to conventional ESCs maintained in serum. In serum, female ESCs are hypomethyated similarly to male ESCs in 2i, and DNA methylation is further reduced in 2i. Regions with elevated DNA methylation in 2i strongly correlate with the presence of H3K9me3 on endogenous retroviruses (ERVs) and imprinted loci. The methylome of male ESCs in serum parallels postimplantation blastocyst cells, while 2i stalls ESCs in a hypomethylated, ICM-like state. WGBS analysis during adaptation of 2i ESCs to serum suggests that deposition of DNA methylation is largely random, while loss of DNA methylation during reversion to 2i occurs passively, initiating at TET1 binding sites. Together, our analysis provides insight into DNA methylation dynamics in cultured ESCs paralleling early developmental processes.


Marks, Hendrik (4-kant)Stunnenberg

            (Hendrik Marks)                                                                                                                   (Henk Stunnenberg)


Whole-Genome Bisulfite Sequencing of Two Distinct Interconvertible DNA Methylomes of Mouse Embryonic Stem Cells. Habibi E, Brinkman AB, Arand J, Kroeze LI, Kerstens HH, Matarese F, Lepikhov K, Gut M, Brun-Heath I, Hubner NC, Benedetti R, Altucci L, Jansen JH, Walter J, Gut IG, Marks H, Stunnenberg HG. Cell Stem Cell. 2013 Jul 10. doi:pii: S1934-5909(13)00260-9. 10.1016/j.stem.2013.06.002. [Epub ahead of print] PMID: 23850244 [PubMed - as supplied by publisher]


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