Trancriptome-wide mapping of TET2-regulated m5C sites in mouse embryonic stem cells (mESCs)
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ABSTRACT:
PROVIDER: PRJNA576264 | ENA |
REPOSITORIES: ENA
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Project description:We mapped the transcriptome-wide distribution of m5C sites, which are under the regulation TET2, using immunoprecipitation with specific anti-5mC antibodies followed by next-generation high-throughput sequencing in Tet2 KO mESCs in comparison to wild-type mESCs. Our data revealed that TET2-mediated m5C modifications primarily localize in 3’UTR of mRNA. Moreover, transcripts containing TET2-regulated m5C sites are stabilized with longer lifetime in Tet2 deficiency mESCs, indicated by the lifetime-seq.
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Project description:Mutation of TET2 drives myeloid malignancy progression. TET2 deficiency is known to cause a globally opened chromatin and activation of genes contributing to aberrant HSPC self-renewal. We show here that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C), installed by NSUN2, can be recognized by the methyl-CpG-binding domain protein MBD6, which guides deubiquitylation of nearby histone H2AK119ub to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitylation. Thereby, TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription in stem cells. TET2 mutant human leukemia became dependent on this gene activation pathway, with MBD6 silencing selectively inhibits proliferation of TET2 mutant leukemia in vitro and in vivo. Altogether, our findings reveal a previously unknown chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.
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Project description:Mutation of TET2 drives myeloid malignancy progression. TET2 deficiency is known to cause a globally opened chromatin and activation of genes contributing to aberrant HSPC self-renewal. We show here that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C), installed by NSUN2, can be recognized by the methyl-CpG-binding domain protein MBD6, which guides deubiquitylation of nearby histone H2AK119ub to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitylation. Thereby, TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription in stem cells. TET2 mutant human leukemia became dependent on this gene activation pathway, with MBD6 silencing selectively inhibits proliferation of TET2 mutant leukemia in vitro and in vivo. Altogether, our findings reveal a previously unknown chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.
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