RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells
2018
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
Paraspecklecomponent 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 deacetylasesand 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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