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Players in the silencing of retroviral DNAs in embryonic stem cells

Embryonic stem (ES) cells potently repress retroviral infection through transcriptional silencing of the newly established proviral DNAs. We have characterized two distinct types of silencing in embryonic mouse cells infected by the Moloney murine leukemia virus (MLV): a highly efficient one targeted to the proline tRNA primer binding site (PBSpro) on the MLV genome, and a less efficient one occurring independently of the PBS. We determined that the PBS-specific silencing is mediated by TRIM28 (Kap-1), a known transcriptional silencer, tethered to the DNA by ZFP809, one of the dozens of zinc finger proteins encoded in the mammalian genome. At least two more components, HP1gamma and EBP1, are implicated in this silencing. We have also begun characterizing a non-PBS directed silencing complex acting more broadly on incoming viral DNAs in ES cells. We suggest that a major player in this process is Yin Yang1 (YY1), a GLI-Kruppel zinc finger protein, ubiquitously expressed and highly conserved between species. We show by ChIP that YY1 binds the LTR of both exogenous and endogenous retroviruses in ES cells. Deletion of the YY1 binding site from the MLV-LTR increased expression of the provirus at least four fold over that of the wild-type virus. Moreover, in YY1 KD cells the expression of the IAP (class II) endogenous retroviruses was remarkably upregulated.

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Correspondence to Stephen P Goff.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( https://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

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Schlesinger, S., Wang, G., Lee, A. et al. Players in the silencing of retroviral DNAs in embryonic stem cells. Retrovirology 10, O13 (2013). https://doi.org/10.1186/1742-4690-10-S1-O13

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Keywords

  • Embryonic Stem Cell
  • Zinc Finger Protein
  • Murine Leukemia Virus
  • Proviral DNAs
  • Primer Binding Site