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Published October 2, 2024 | Version v1
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RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis

Creators

  • 1. University of Chicago
  • 2. University of Texas

Description

Mutation of tet methylcytosine dioxygenase 2 (encoded by TET2) drives myeloid malignancy initiation and progression. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant haematopoietic stem cell self-renewal. However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukaemic cells and haematopoietic stem and progenitor cells5 is inconsistent with the designated role of DNA 5-methylcytosine oxidation of TET2. Here we show that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C) can be recognized by the methyl-CpG-binding-domain protein MBD6, which guides deubiquitination of nearby monoubiquitinated Lys119 of histone H2A (H2AK119ub) to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. TET2 depletion thereby leads to globally decreased H2AK119ub, more open chromatin and increased transcription in stem cells. TET2-mutant human leukaemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocking proliferation of TET2-mutant leukaemic cells and largely reversing the haematopoiesis defects caused by Tet2 loss in mouse models. Together, our findings reveal a 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.

Data availability

High-throughput sequencing data can be accessed at the GEO under accession number GSE241347. Previously published sequencing data that were reanalysed here are available under accession codes GSE103269, GSE48518, GSE181698 and GSE48519. All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

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Additional details

Identifiers

DOI
10.1038/s41586-024-07969-x
Other
oai:uchicago.tind.io:13650

Funding

National Institutes of Health
RM1 HG008935
Ludwig Cancer Center
National Institutes of Health
R01 HL174477
National Institutes of Health
R01 HL146664
National Institutes of Health
R01 HL145883

UChicago Information

Division(s)
Biological Sciences Division, Physical Sciences Division
Department(s)
Biochemistry and Molecular Biology, Chemistry
Center(s) or Institute(s)
Institute for Biophysical Dynamics