Article abstract
Nature Cell Biology 10, 1280 - 1290 (2008)
Published online: 5 October 2008 | doi:10.1038/ncb1786
Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5
Ray Kit Ng1,2, Wendy Dean1, Claire Dawson1, Diana Lucifero1, Zofia Madeja1,2, Wolf Reik1,2 & Myriam Hemberger1,2
Abstract
Mouse ES cells can differentiate into all three germ layers of the embryo but are generally excluded from the trophoblast lineage. Here we show that ES cells deficient in DNA methylation can differentiate efficiently into trophoblast derivatives. In a genome-wide screen we identified the transcription factor Elf5 as methylated and repressed in ES cells, and hypomethylated and expressed in TS and methylation-deficient ES cells. Elf5 creates a positive-feedback loop with the TS cell determinants Cdx2 and Eomes that is restricted to the trophoblast lineage by epigenetic regulation of Elf5. Importantly, the late-acting function of Elf5 allows initial plasticity and regulation in the early blastocyst. Thus, Elf5 functions as a gatekeeper, downstream of initial lineage determination, to reinforce commitment to the trophoblast lineage or to abort this pathway in epiblast cells. This epigenetic restriction of cell lineage fate provides a molecular mechanism for Waddington's concept of canalization of developmental pathways.
- Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB22 3AT, UK.
- Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK.
Correspondence to: Myriam Hemberger1,2 e-mail: myriam.hemberger@bbsrc.ac.uk
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