Letter | Published:

Co-repressor CBFA2T2 regulates pluripotency and germline development

Nature volume 534, pages 387390 (16 June 2016) | Download Citation


Developmental specification of germ cells lies at the heart of inheritance, as germ cells contain all of the genetic and epigenetic information transmitted between generations. The critical developmental event distinguishing germline from somatic lineages is the differentiation of primordial germ cells (PGCs)1,2, precursors of sex-specific gametes that produce an entire organism upon fertilization. Germ cells toggle between uni- and pluripotent states as they exhibit their own ‘latent’ form of pluripotency. For example, PGCs express a number of transcription factors in common with embryonic stem (ES) cells, including OCT4 (encoded by Pou5f1), SOX2, NANOG and PRDM14 (refs 2, 3, 4). A biochemical mechanism by which these transcription factors converge on chromatin to produce the dramatic rearrangements underlying ES-cell- and PGC-specific transcriptional programs remains poorly understood. Here we identify a novel co-repressor protein, CBFA2T2, that regulates pluripotency and germline specification in mice. Cbfa2t2/ mice display severe defects in PGC maturation and epigenetic reprogramming. CBFA2T2 forms a biochemical complex with PRDM14, a germline-specific transcription factor. Mechanistically, CBFA2T2 oligomerizes to form a scaffold upon which PRDM14 and OCT4 are stabilized on chromatin. Thus, in contrast to the traditional ‘passenger’ role of a co-repressor, CBFA2T2 functions synergistically with transcription factors at the crossroads of the fundamental developmental plasticity between uni- and pluripotency.

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Gene Expression Omnibus

Data deposits

Sequencing data have been deposited in the Gene Expression Omnibus under accession number GSE71676.


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We thank P. Andrews and X.-J. Sun for providing plasmids. We are grateful to L. Vales, M. E. Torres-Padilla and L. Bu for critical comments, H. Zheng for MS analysis, and D. Hernandez, C. Leek, M. Yamaji, A. Paradkar and M. Alu for excellent technical assistance. The work was supported by the Howard Hughes Medical Institute (HHMI) and National Institutes of Health (NIH; RO1GM064844-12) (D.R.). B.A.G. acknowledges funding from NIH grant R01GM110174. T.T. was supported by the HHMI, NIH, Starr Foundation, and Tri-Institutional Stem Cell Initiative. M.Y. was a recipient of a Japan Society for the Promotion of Science (JSPS) Research Fellowship.

Author information


  1. Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA

    • Shengjiang Tu
    • , Varun Narendra
    • , Luis Alejandro Rojas
    •  & Danny Reinberg
  2. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA

    • Shengjiang Tu
    • , Varun Narendra
    • , Luis Alejandro Rojas
    •  & Danny Reinberg
  3. Howard Hughes Medical Institute, Laboratory for RNA Molecular Biology, The Rockefeller University, New York, New York 10065, USA

    • Masashi Yamaji
    •  & Thomas Tuschl
  4. Skirball Institute of Biomolecular Medicine, Department of Cell Biology and Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University School of Medicine, New York, New York 10016, USA

    • Simon E. Vidal
    •  & Matthias Stadtfeld
  5. Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Xiaoshi Wang
    •  & Benjamin A. Garcia
  6. Rodent Genetic Engineering Core, NYU School of Medicine, New York, New York 10016, USA

    • Sang Yong Kim


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S.T. designed and performed majority of experiments; V.N. analysed ChIP-seq and RNA-seq data; S.E.V., S.T. and M.S. performed iPSC reprogramming experiments; X.W. and B.A.G. quantified histone modifications. S.Y.K. did CRISPR zygotic injection. S.T., S.Y.K., M.Y. and L.A.R. characterized mice. M.Y., S.T. and T.T. designed and performed PGC experiments. S.T., V.N., M.Y. and D.R. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Danny Reinberg.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This table contains PRDM14 and CBFA2T2 target genes identified by ChIP-seq in NCCIT cell.

  2. 2.

    Supplementary Table 2

    This table contains differentially expressed genes in Prdm14 and Cbfa2t2 Knockout lines.

  3. 3.

    Supplementary Table 3

    This table contains qPCR and PCR primers used in ChIP-qPCR and off-target verification.

  4. 4.

    Supplementary Table 4

    This table contains PRDM14 and CBFA2T2 target genes identified by ChIP-seq in mouse ESC.

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figure 1, the uncropped western blot images.

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