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. Litzow; Young-In Chi; Ann M Bode; Chunhui Liu; Haojie Huang; Daihong Liu; Guido Marcucci; Shujun Liu; Li Yu

doi:10.1038/s41467-019-12960-6

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

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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 language	English (US)
Article number	5051
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12960-6
State	Published - Dec 1 2019

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© 2019, The Author(s).

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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), Article 5051. https://doi.org/10.1038/s41467-019-12960-6

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, Litzow, MR, Chi, Y-I, Bode, AM, Liu, C, Huang, H, Liu, D, Marcucci, G, Liu, S & Yu, L 2019, 'Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia', Nature communications, vol. 10, no. 1, 5051. https://doi.org/10.1038/s41467-019-12960-6

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title = "Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-019-12960-6",

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AU - Dou, Liping

AU - Yan, Fei

AU - Pang, JiuXia

AU - Zheng, Dehua

AU - Li, Dandan

AU - Gao, Li

AU - Wang, Lijun

AU - Xu, Yihan

AU - Shi, Jinlong

AU - Wang, Qian

AU - Zhou, Lei

AU - Shen, Na

AU - Singh, Puja

AU - Wang, Lili

AU - Li, Yonghui

AU - Gao, Yvchi

AU - Liu, Tao

AU - Chen, Chongjian

AU - Al-Kali, Aref

AU - Litzow, Mark R.

AU - Chi, Young-In

AU - Bode, Ann M

AU - Liu, Chunhui

AU - Huang, Haojie

AU - Liu, Daihong

AU - Marcucci, Guido

AU - Liu, Shujun

AU - Yu, Li

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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

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