RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells
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ISSN: 1061-4036
E-ISSN: 1546-1718
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Springer Nature
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Abstract
Ten-eleven translocation (TET) proteins play key roles in the regulation of DNA-methylation status by oxidizing 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), which can both serve as a stable epigenetic mark and participate in active demethylation. Unlike the other members of the TET family, TET2 does not contain a DNA-binding domain, and it remains unclear how it is recruited to chromatin. Here we show that TET2 is recruited by the RNA-binding protein Paraspeckle component 1 (PSPC1) through transcriptionally active loci, including endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) have been co-opted by mammalian genomes as stage- and tissue-specific transcriptional regulatory modules. We found that PSPC1 and TET2 contribute to ERVL and ERVL-associated gene regulation by both transcriptional repression via histone deacetylases and post-transcriptional destabilization of RNAs through 5hmC modification. Our findings provide evidence for a functional role of transcriptionally active ERVs as specific docking sites for RNA epigenetic modulation and gene regulation
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Guallar, D., Bi, X., Pardavila, J.A. et al. RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells. Nat Genet 50, 443–451 (2018). https://doi.org/10.1038/s41588-018-0060-9
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https://doi.org/10.1038/s41588-018-0060-9Sponsors
We thank Y. Kurihara for PSPC1 constructs, T. Macfarlan for the Zfp352-luciferase reporter construct, R. Jaenisch for the Tet-TKO ESC line, D. Trono for the Trim28-cKO line, and D.M. Gilbert and Y. Shinkai for the Ehmt2-cKO line. We also thank the medical illustrator J. Gregory from Icahn School of Medicine at Mount Sinai for the model drawing. This research was funded by the US National Institutes of Health (NIH) (grants 1R01-GM095942 and R21HD087722 to J.W.; grant R01HL112294 to M.X.) and the Empire State Stem Cell Fund through the New York State Department of Health (NYSTEM) (grants C028103 and C028121 to J.W.). J.W. is a recipient of an Irma T. Hirschl and Weill-Caulier Trusts Career Scientist Award, and M.F. is a recipient of a Ramón y Cajal contract (RYC-2014-16779) from the Ministerio de Economía y Competitividad of Spain. The research from the Shen laboratory is supported by the National Natural Science Foundation of China (31471219 and 31428010) and the Center for Life Sciences (CLS) at Tsinghua University. Additional support was provided by the Agencia Estatal de Investigación (BFU2016-80899-P to M.F.) (AEI/FEDER, UE) and the Consellería de Cultura, Educación e Ordenación Universitaria (ED431F 2016/016 to M.F.)