Cell stem cell, 2016-07, Vol.19 (1), p.81-94
2016
Details
- Autor(en) / Beteiligte
- Titel
- Activation of Endogenous Retroviruses in Dnmt1−/− ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA
- Ist Teil von
- Cell stem cell, 2016-07, Vol.19 (1), p.81-94
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. [Display omitted] •Acute depletion of Dnmt1, but not Np95, leads to activation of IAP proviral sequences•Global DNA demethylation occurs to a similar extent following deletions of Np95 or Dnmt1•Hemimethylated DNA accumulation after Dnmt1 deletion prolongs NP95 binding•Prolonged NP95 binding disrupts SETDB1 recruitment and inhibits IAP repression Sharif et al. show that transient derepression of proviral loci following acute depletion of Dnmt1 in ESCs is not dependent on loss of DNA methylation per se. Rather, elevated levels of hemimethylated DNA promote prolonged binding of NP95, which in turn disrupts SETDB1-dependent deposition of the repressive histone mark H3K9me3.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1934-5909eISSN: 1875-9777DOI: 10.1016/j.stem.2016.03.013Titel-ID: cdi_proquest_miscellaneous_1802744227
- Format
- –
- Schlagworte
- Animals, Cell Differentiation, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases - metabolism, DNA - metabolism, DNA Methylation - genetics, Endogenous Retroviruses - metabolism, Female, Gene Dosage, Gene Expression Regulation, Developmental, Gene Silencing, Genes, Intracisternal A-Particle, Genetic Loci, Histone-Lysine N-Methyltransferase - metabolism, Histones - metabolism, Lysine - metabolism, Mice, Mice, Knockout, Models, Biological, Mouse Embryonic Stem Cells - metabolism, Mutation - genetics, Nuclear Proteins - chemistry, Nuclear Proteins - metabolism, Placenta - metabolism, Pregnancy, Protein Binding, Protein Domains, Trophoblasts - metabolism, Virus Activation