RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis

• 成果类型: Article
• 署名作者: Zou, Zhongyu; Dou, Xiaoyang; Li, Ying; Zhang, Zijie; Wang, Juan; Gao, Boyang; Xiao, Yu; Wang, Yiding; Zhao, Lijie; Sun, Chenxi; Liu, Qinzhe; Yu, Xianbin; Wang, Hao; Hong, Juyeong; Dai, Qing; Yang, Feng-Chun; Xu, Mingjiang; He, Chuan
• 署名单位: University of Chicago; Howard Hughes Medical Institute; University of Chicago; University of Texas System; University of Texas at San Antonio; University of Chicago; University of Chicago; University of Texas System; University of Texas at San Antonio; University of Texas System; University of Texas at San Antonio
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3787
• DOI: 10.1038/s41586-024-07969-x
• 发表日期: 2024-10-01
• 页码: 986-+
• 关键词: cell self-renewal; histone h2a; dna; mutations; 5-methylcytosine; demethylation; proteins; genome; 5-hydroxymethylcytosine; expression

摘要

Mutation of tet methylcytosine dioxygenase 2 (encoded by TET2) drives myeloid malignancy initiation and progression(1-3). TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant haematopoietic stem cell self-renewal(4,5). However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukaemic cells and haematopoietic stem and progenitor cells(5) is inconsistent with the designated role of DNA 5-methylcytosine oxidation of TET2. Here we show that chromatin-associated retrotransposon RNA 5-methylcytosine (m(5)C) 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 m(5)C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.