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Sequence-specific regulator Prdm14 safeguards mouse ESCs from entering extraembryonic endoderm fates

Nature Structural & Molecular Biology volume 18, pages 120–127 (2011)Cite this article

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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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Figure 1: Prdm14 downregulation in mESCs results in spontaneous differentiation to ExEn fates.
Figure 2: Analysis of gene expression changes upon Prdm14 knockdown in mESCs reveals upregulation of ExEn genes.
Figure 3: Failure to downregulate Prdm14 during embryoid body formation from mESCs impairs induction of ExEn fates.
Figure 4: Prdm14 targets loci encoding ExEn genes and mESC transcription factors.
Figure 5: Genome-wide analysis of Prdm14 chromatin occupancy.
Figure 6: Prdm14 recognizes a unique DNA sequence motif.
Figure 7: Model for Prdm14 function in mESC gene regulation.

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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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Authors and Affiliations

  1. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA

    Ziyang Ma, Tomek Swigut, Alvaro Rada-Iglesias & Joanna Wysocka

  2. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

    Anton Valouev

  3. Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, USA

    Joanna Wysocka

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  1. Ziyang Ma
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Contributions

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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Correspondence to Joanna Wysocka.

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Supplementary information

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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