Activation of Endogenous Retroviruses in Dnmt1−/− ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA

Jafar Sharif, Takaho A. Endo, Manabu Nakayama, Mohammad M. Karimi, Midori Shimada, Kayoko Katsuyama, Preeti Goyal, Julie Brind'Amour, Ming An Sun, Zhixiong Sun, Tomoyuki Ishikura, Yoko Mizutani-Koseki, Osamu Ohara, Yoichi Shinkai, Makoto Nakanishi, Hehuang Xie, Matthew C. Lorincz, Haruhiko Koseki

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27 Citations (Scopus)

Abstract

Repression of endogenous retroviruses (ERVs) in mammals involves several epigenetic mechanisms. Acute loss of the maintenance methyltransferase Dnmt1 induces widespread DNA demethylation and transcriptional activation of ERVs, including CpG-rich IAP (intracisternal A particle) proviruses. Here, we show that this effect is not due simply to a loss of DNA methylation. Conditional deletions reveal that both Dnmt1 and Np95 are essential for maintenance DNA methylation. However, while IAPs are derepressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these ERVs remain silenced when Np95 is deleted alone or in combination with Dnmt1. This paradoxical phenotype results from an ectopic interaction between NP95 and the H3K9 methyltransferase SETDB1. Normally, SETDB1 maintains silencing of IAPs, but in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA transiently disrupts SETDB1-dependent H3K9me3 deposition. Thus, our observations reveal an unexpected antagonistic interplay between two repressive pathways involved in retroviral silencing in mammalian cells.

Original languageEnglish
Pages (from-to)81-94
Number of pages14
JournalCell Stem Cell
Volume19
Issue number1
DOIs
Publication statusPublished - 1 Jul 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Sharif, J., Endo, T. A., Nakayama, M., Karimi, M. M., Shimada, M., Katsuyama, K., Goyal, P., Brind'Amour, J., Sun, M. A., Sun, Z., Ishikura, T., Mizutani-Koseki, Y., Ohara, O., Shinkai, Y., Nakanishi, M., Xie, H., Lorincz, M. C., & Koseki, H. (2016). Activation of Endogenous Retroviruses in Dnmt1−/− ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA. Cell Stem Cell, 19(1), 81-94. https://doi.org/10.1016/j.stem.2016.03.013