Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia

Liping Dou, Fei Yan, Jiuxia Pang, Dehua Zheng, Dandan Li, Li Gao, Lijun Wang, Yihan Xu, Jinlong Shi, Qian Wang, Lei Zhou, Na Shen, Puja Singh, Lili Wang, Yonghui Li, Yvchi Gao, Tao Liu, Chongjian Chen, Aref Al-Kali, Mark R. LitzowYoung In Chi, Ann M. Bode, Chunhui Liu, Haojie Huang, Daihong Liu, Guido Marcucci, Shujun Liu, Li Yu

Research output: Contribution to journalArticle

Abstract

The oncogenic fusion protein AML1-ETO retains the ability of AML1 to interact with the enhancer core DNA sequences, but blocks AML1-dependent transcription. Previous studies have shown that post-translational modification of AML1-ETO may play a role in its regulation. Here we report that AML1-ETO-positive patients, with high histone lysine methyltransferase Enhancer of zeste homolog 1 (EZH1) expression, show a worse overall survival than those with lower EZH1 expression. EZH1 knockdown impairs survival and proliferation of AML1-ETO-expressing cells in vitro and in vivo. We find that EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43). This requires the EZH1 SET domain, which augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO-repressive activity. These findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia.

Original languageEnglish (US)
Article number5051
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia'. Together they form a unique fingerprint.

  • Cite this

    Dou, L., Yan, F., Pang, J., Zheng, D., Li, D., Gao, L., Wang, L., Xu, Y., Shi, J., Wang, Q., Zhou, L., Shen, N., Singh, P., Wang, L., Li, Y., Gao, Y., Liu, T., Chen, C., Al-Kali, A., ... Yu, L. (2019). Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia. Nature communications, 10(1), [5051]. https://doi.org/10.1038/s41467-019-12960-6