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Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5
Open accessAbstract
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.
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Cites
A bivalent chromatin structure marks key developmental genes in embryonic stem cells
Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.041 · Cited by 5,361
Stability and flexibility of epigenetic gene regulation in mammalian development
Reik, W. (2007) · Nature · doi:10.1038/nature05918 · Cited by 1,963 · cited 1×
“Once fixed, lineage determination must be accompanied by epigenetic modifications that ensure the stable inheritance of cell fat”
BackgroundSelf-citationDe novo DNA cytosine methyltransferase activities in mouse embryonic stem cells
Lei, H., Oh, S. P., Okano, M., Jüttermann, R., Goss, K. A., Jaenisch, R., & Li, E. (1996) · Development · doi:10.1242/dev.122.10.3195 · Cited by 816
Choi, Y. S., & Sinha, S. (2006) · Biochemical Journal · doi:10.1042/bj20060375 · Cited by 32
Cited by
DNA methylation: roles in mammalian development
Smith, Z. D., & Meissner, A. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3354 · Cited by 3,045
Koh, K. P., Yabuuchi, A., Rao, S., Huang, Y., Cunniff, K., Nardone, J., Laiho, A., Tahiliani, M., Sommer, C. A., Mostoslavsky, G., et al. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.01.008 · Cited by 776
Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa
Brykczynska, U., Hisano, M., Erkek, S., Ramos, L., Oakeley, E. J., Roloff, T. C., Beisel, C., Schübeler, D., Stadler, M. B., & Peters, A. H. F. M. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1821 · Cited by 680
Xu, Y., Wu, F., Tan, L., Kong, L., Xiong, L., Deng, J., Barbera, A. J., Zheng, L., Zhang, H., Huang, S., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.04.005 · Cited by 632
Epigenetic mechanisms that underpin metabolic and cardiovascular diseases
Gluckman, P. D., Hanson, M. A., Buklijas, T., Low, F. M., & Beedle, A. S. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.102 · Cited by 627
Metadata
- Authors
- Ng, R. K., Dean, W., Dawson, C., Lucifero, D., Madeja, Z., Reik, W., & Hemberger, M.
- Venue
- Nature Cell Biology
- Published
- 2008-10-05
- Volume
- 10
- Issue
- 11
- Pages
- 1280-1290
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2088237277
- Cited by
- 368
- References
- 4
- FWCI
- 10.30
- Type
- journal article
- Language
- en
- Open access
- green
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- Ng, R. K., Dean, W., Dawson, C., Lucifero, D., Madeja, Z., Reik, W., & Hemberger, M. (2008). Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nature Cell Biology. https://doi.org/10.1038/ncb1786
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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