Abstract
Prdm14 is a PR-domain and zinc-finger protein whose expression is restricted to the pluripotent cells of the early embryo, embryonic stem cells (ESCs), and germ cells. Here, we show that Prdm14 safeguards mouse ESC (mESC) maintenance by preventing induction of extraembryonic endoderm (ExEn) fates. Conversely, Prdm14 overexpression impairs ExEn differentiation during embryoid body formation. Prdm14 occupies and represses genomic loci encoding ExEn differentiation factors, while also binding to and promoting expression of genes associated with mESC self-renewal. Prdm14-associated genomic regions substantially overlap those occupied by Nanog and Oct4, are enriched in a chromatin signature associated with distal regulatory elements and contain a unique DNA-sequence motif recognized by Prdm14 in vitro. Our work identifies a new member of the mESC transcriptional network, Prdm14, which plays a dual role as a context-dependent transcriptional repressor or activator.
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Acknowledgements
We thank members of the Wysocka laboratory for helpful discussions and E. Grow, K. Murata, A. Roos, S. A. Brugmann, C. Buecker and A. Sidow for critical readings of the manuscript. This work was supported by the CIRM New Faculty Award (RN1 00579-1) and W. M. Keck Distinguished Young Scholar Award for J.W.
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Z.M. and J.W. conceived the project; Z.M. conducted experiments with input from J.W.; T.S. analyzed the RNA-seq data and contributed ideas; A.V., Z.M. and A.R.-I. analyzed ChIP-seq datasets. J.W. and Z.M. wrote the manuscript.
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Supplementary Text and Figures
Supplementary Figures 1–10, Supplementary Table 1 and Supplementary Table 2 (PDF 1275 kb)
Supplementary Data 1
Genes affected by Prdm14 downregulation (XLS 113 kb)
Supplementary Data 2
FH-Prdm14 ChIP-seq enriched regions (XLS 243 kb)
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Ma, Z., Swigut, T., Valouev, A. et al. Sequence-specific regulator Prdm14 safeguards mouse ESCs from entering extraembryonic endoderm fates. Nat Struct Mol Biol 18, 120–127 (2011). https://doi.org/10.1038/nsmb.2000
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DOI: https://doi.org/10.1038/nsmb.2000
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