Oncotarget

Research Papers:

Multiple regulatory aspects of histone methyltransferase EZH2 in Pb-induced neurotoxicity

Wei-Zhen Xue, Xiaozhen Gu, Yulan Wu, Danyang Li, Yi Xu _ and Hui-Li Wang

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Oncotarget. 2017; 8:85169-85184. https://doi.org/10.18632/oncotarget.19615

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Abstract

Wei-Zhen Xue1,*, Xiaozhen Gu1,*, Yulan Wu1, Danyang Li1, Yi Xu1 and Hui-Li Wang1

1School of Food Science and Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China

*These authors have contributed equally to this work

Correspondence to:

Yi Xu, email: xuyixuyi3734@163.com

Hui-Li Wang, email: wanghl@hfut.edu.cn

Keywords: Pb, neurotoxicity, EZH2, chromatin immunoprecipitation, PRC2

Received: September 18, 2016     Accepted: July 06, 2017     Published: July 27, 2017

ABSTRACT

Pb is a pervasive environmental threat to human health. Although remarkable progress has been made in its neurotoxicity, the precise molecular mechanisms underlying this widespread toxicant still remain elusive. In this study, the detailed roles of EZH2, a transcriptional repressor, in the regulation of Pb-led neurotoxicity were investigated, highlighting its sub-functionalization, compartmentalization, functional chaperones and downstream partners. Based on the findings, EZH2’s protein levels were significantly reduced in response to Pb treatment; EZH2’s gain-of-function trials recovered the dampened neurite outgrowth; EZH2’ recruitment to ploycomb complex, as well as its interaction with cytosolic Vav1, was altered in a distinct manner, suggesting that EZH2’s multiple roles were markedly redistributed in this context; EZH2’s cytosolic and nuclear presence differed in their respective response towards Pb treatment; EZH2 directly occupied the promoters of EGR2, NGFR and CaMKK2, genes responsible for various nerve functions and repair mechanisms, and essentially contributed to their aberrant expression. It indicated that EZH2 mediated the dynamic changes of a cascade of key molecules and consequently the related neurological impairments. In summary, EZH2 emerges as a central player to regulate Pb-led neurotoxicity in a transcriptionally dependent and independent manner, and thereby provided a promising molecular target for medical intervention.


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