RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis

Zhongyu Zou, Xiaoyang Dou, Ying Li, Zijie Zhang, Juan Wang, Boyang Gao, Yu Xiao, Yiding Wang, Lijie Zhao, Chenxi Sun, Qinzhe Liu, Xianbin Yu, Hao Wang, Juyeong Hong, Qing Dai, Feng-Chun Yang, Mingjiang Xu () and Chuan He ()
Additional contact information
Zhongyu Zou: The University of Chicago
Xiaoyang Dou: The University of Chicago
Ying Li: University of Texas Health Science Center at San Antonio
Zijie Zhang: The University of Chicago
Juan Wang: University of Texas Health Science Center at San Antonio
Boyang Gao: The University of Chicago
Yu Xiao: The University of Chicago
Yiding Wang: The University of Chicago
Lijie Zhao: The University of Chicago
Chenxi Sun: The University of Chicago
Qinzhe Liu: The University of Chicago
Xianbin Yu: The University of Chicago
Hao Wang: The University of Chicago
Juyeong Hong: University of Texas Health Science Center at San Antonio
Qing Dai: The University of Chicago
Feng-Chun Yang: University of Texas Health Science Center at San Antonio
Mingjiang Xu: University of Texas Health Science Center at San Antonio
Chuan He: The University of Chicago

Nature, 2024, vol. 634, issue 8035, 986-994

Abstract: Abstract Mutation of tet methylcytosine dioxygenase 2 (encoded by TET2) drives myeloid malignancy initiation and progression1–3. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant haematopoietic stem cell self-renewal4,5. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07969-x

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