The NuRD component Mbd3 is required for pluripotency of embryonic stem cells

Abstract

Cells of early mammalian embryos have the potential to develop into any adult cell type, and are thus said to be pluripotent. Pluripotency is lost during embryogenesis as cells commit to specific developmental pathways. Although restriction of developmental potential is often associated with repression of inappropriate genetic programmes1, the role of epigenetic silencing during early lineage commitment remains undefined. Here, we used mouse embryonic stem cells to study the function of epigenetic silencing in pluripotent cells. Embryonic stem cells lacking Mbd3 — a component of the nucleosome remodelling and histone deacetylation (NuRD) complex2,3 — were viable but failed to completely silence genes that are expressed before implantation of the embryo. Mbd3-deficient embryonic stem cells could be maintained in the absence of leukaemia inhibitory factor (LIF) and could initiate differentiation in embryoid bodies or chimeric embryos, but failed to commit to developmental lineages. Our findings define a role for epigenetic silencing in the cell-fate commitment of pluripotent cells.

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Figure 1: Characterization of Mbd3−/− embryonic stem cells.
Figure 2: Differentiation defects in Mbd3−/− embryonic stem cells.
Figure 3: LIF-independent maintenance of Mbd3−/− embryonic stem cells.
Figure 4: Failure of Mbd3−/− embryonic stem cells to differentiate in chimeric embryos.

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Acknowledgements

We are grateful to M. Osawa and S. Nishikawa for instruction on the single-cell cDNA amplification technique. We also thank J. Back and R. Wilkie for technical assistance; R. McLay, G. Russell and J. Agnew for chimaera production; and A. Smith, I. Chambers, T. Kunath, J. Kawaguchi and N. Reynolds for advice, discussions and comments on the manuscript. K.K. was the recipient of a postdoctoral fellowship from the Japanese Society for the Promotion of Science, and I.M.C. was the recipient of a University of Edinburgh School of Biological Sciences PhD studentship. This work was funded by the Wellcome Trust, the UK Medical Research Council, and Biotechnology and Biological Sciences Research Council (BBSRC) UK–Japan Partnering Award.

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Correspondence to Brian Hendrich.

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Supplementary figures S1, S2 and S3 plus Supplementary table S1 (PDF 399 kb)

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Kaji, K., Caballero, I., MacLeod, R. et al. The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol 8, 285–292 (2006). https://doi.org/10.1038/ncb1372

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