E-MTAB-1754 - DNA Methylation Profiles Define Stem Cell Identity and Reveal a Tight Embryonic-Extraembryonic Lineage Boundary
Released on 3 July 2013, last updated on 4 July 2013
Embryonic (ES) and epiblast (EpiSC) stem cells are pluripotent but committed to an embryonic lineage fate. Conversely, trophoblast (TS) a nd extraembryonic endoderm (XEN) stem cells contribute predominantly to tissues of the placenta and yolk sac, respectively. Here we show that each of these four stem cell types is defined by a unique DNA methylation profile. Despite their distinct developmental origin, TS and XEN cells share key epigenomic hallmarks, chiefly characterized by robust DNA methylation of embryo-specific developmental regulators, as well as a subordinate role of 5-hydroxymethylation. We also observe a substantial methylation reinforcement of pre-existing epigenetic repressive marks that specifically occurs in extraembryonic stem cells compared to in vivo tissue, presumably due to continued high Dnmt3b expression levels. These differences establish a major epigenetic barrier between the embryonic and extraembryonic stem cell types. In addition, epigenetic lineage boundaries also separate the two extraembryonic stem cell types by mutual repression of key lineage-specific transcription factors. Thus, global DNA methylation patterns are a defining feature of each stem cell type that underpin lineage commitment and differentiative potency of early embryo-derived stem cells. Our detailed methylation profiles identify a cohort of developmentally regulated sequence elements, such as orphan CpG islands, that will be most valuable to uncover novel transcriptional regulators and pivotal ‘‘gatekeeper’’ genes in pluripotency and lineage differentiation.
methylation profiling by high throughput sequencing, binding site identification, cell type comparison, in vitro
DNA methylation profiles define stem cell identity and reveal a tight embryonic-extraembryonic lineage boundary. Senner CE, Krueger F, Oxley D, Andrews S, Hemberger M. Stem Cells 30(12):2732-2745 (2012), Europe PMC 23034951