Embryonic stem cells use ZFP809 to silence retroviral DNAs
Open accessAbstract
Embryonic stem cells (ESCs) and other primitive stem cells of mice have been known for more than 30 years to potently block retrovirus replication. Infection of ESCs by the murine leukaemia viruses (MLVs) results in the normal establishment of integrated proviral DNA, but this DNA is then transcriptionally silenced, preventing further viral spread. The repression is largely mediated by trans-acting factors that recognize a conserved sequence element termed the primer binding site, an 18-base pair sequence complementary to the 3' end of a cellular transfer RNA. A specific tRNA is annealed to the primer binding site sequence of the viral genomic RNA, and is used to prime DNA synthesis. This same sequence in the context of the integrated proviral DNA is targeted for silencing in ESCs. We have recently shown that a large protein complex binding to the primer binding site in ESCs contains TRIM28 (refs 8, 9), a well-characterized transcriptional co-repressor. An important question remains as to the identity of the factor that directly recognizes integrated retroviral DNAs and recruits TRIM28 to mediate their specific silencing. Here we identify the zinc finger protein ZFP809 as the recognition molecule that bridges the integrated proviral DNA and TRIM28. We show that expression of ZFP809 is sufficient to render even differentiated cells highly resistant to MLV infection. Furthermore, we demonstrate that ZFP809 is able to potently block transcription from DNA constructs of human T-cell lymphotropic virus-1 (HTLV-1), which use the same primer tRNA. These results identify ZFP809 as a DNA-binding factor that specifically recognizes a large subset of mammalian retroviruses and retroelements, targeting them for transcriptional silencing. We propose that ZFP809 evolved as a stem-cell-specific retroviral restriction factor, and therefore constitutes a new component of the intrinsic immune system of stem cells.
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Host defense mechanisms recognize retrotransposon DNA sequences and induce heterochromatization at these locations very early in development.
“Host defense mechanisms recognize retrotransposon DNA sequences in their genomes and induce heterochromatization at these locations very early in development23, 24, 25 (Fig. 3).”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [23]
In the main text (page unavailable), the paper reports that ZFP809 recognizes a sequence in integrated retroviral DNA in embryonic stem cells and recruits TRIM28 to silence it. This supports early-development sequence recognition and silencing, but the passages do not establish that heterochromatin forms at those sites or that the mechanism applies broadly to retrotransposon DNA sequences. (LLM, conf=0.86)
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- Authors
- Wolf, D., & Goff, S. P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Goff, Stephen P.
- Venue
- Nature
- Published
- 2009-03-08
- Volume
- 458
- Issue
- 7242
- Pages
- 1201-1204
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2676211
- OpenAlex
- W1986447756
- Cited by
- 388
- References
- 23
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 20 · 2023: 20 · 2022: 23 · 2021: 31 · 2020: 19 · 2019: 15 · 2018: 22 · 2017: 29 · 2016: 27 · 2015: 36 · 2014: 27 · 2013: 26 · 2012: 20
- FWCI
- 8.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R37CA030488)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- embryonic stem cells, retroviral restriction factors, TRIM28, primer binding site, tRNA primer, Moloney murine leukemia virus, HTLV-1, transcriptional repression, zinc finger proteins, proviral integration, viral infection resistance, differentiated cells
- MeSH terms
- Tripartite Motif-Containing Protein 28, Animals, Cell Differentiation, Cell Line, DNA-Binding Proteins, DNA, Viral, Humans, Leukemia Virus, Murine, Nuclear Proteins, Protein Binding, Repressor Proteins, Retroviridae, RNA, Virus Replication, Human T-lymphotropic virus 1, Gene Expression Regulation, Viral, Gene Silencing, Mice, Embryonic Stem Cells
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