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TET2 regulates histone H2AK119ub and leukemogenesis through LTR RNA m5C oxidation [seq_RNA-CLIP]

GSE241345 Mus musculus Expression profiling by high throughput sequencing 8 samples Submitted 2024/07/25 Platform GPL24247
Summary
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.
Published in
RNA m(5)C oxidation by TET2 regulates chromatin state and leukaemogenesis
Zou Z, Dou X, Li Y et al. · Nature 2024 · PMID 39358506 · doi:10.1038/s41586-024-07969-x
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Also filed as BioProject PRJNA1007727 and SRA study SRP456167. Searching any of these in the dataset finder brings you back here.

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