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Nat Genet. 2018 Mar;50(3):443-451. doi: 10.1038/s41588-018-0060-9. Epub 2018 Feb 26.

RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells.

Author information

1
The Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
CiMUS, Universidade de Santiago de Compostela-Health Research Institute (IDIS), Santiago de Compostela, Coruña, Spain.
3
Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China.
4
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China.
5
Department of Chemistry and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA.
6
Department of Animal Biotechnology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China.
7
The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL, USA.
9
Department of Cell Biology and Development, Instituto de Fisiologia Celular, UNAM, Mexico City, Mexico.
10
The Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jianlong.wang@mssm.edu.
11
The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jianlong.wang@mssm.edu.

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.

PMID:
29483655
PMCID:
PMC5862756
DOI:
10.1038/s41588-018-0060-9
[Indexed for MEDLINE]
Free PMC Article

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