Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements

Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements

Replication-dependent canonical histone messenger RNAs (mRNAs) do not terminate with a poly(A) tail at the 3′ end. We previously demonstrated that exposure to arsenic, an environmental carcinogen, induces polyadenylation of canonical histone H3.1 mRNA, causing transformation of human cells in vitro....

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Published in:iScience Vol. 23; no. 9; p. 101518
Main Authors: Chen, Danqi, Chen, Qiao Yi, Wang, Zhenjia, Zhu, Yusha, Kluz, Thomas, Tan, Wuwei, Li, Jinquan, Wu, Feng, Fang, Lei, Zhang, Xiaoru, He, Rongquan, Shen, Steven, Sun, Hong, Zang, Chongzhi, Jin, Chunyuan, Costa, Max
Format: Journal Article
Language:English
Published: United States Elsevier Inc 25-09-2020
Elsevier
Subjects:
Cell Biology
Omics
Toxicology
Toxicology
Omics
Cell Biology
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Summary:Replication-dependent canonical histone messenger RNAs (mRNAs) do not terminate with a poly(A) tail at the 3′ end. We previously demonstrated that exposure to arsenic, an environmental carcinogen, induces polyadenylation of canonical histone H3.1 mRNA, causing transformation of human cells in vitro. Here we report that polyadenylation of H3.1 mRNA increases H3.1 protein, resulting in displacement of histone variant H3.3 at active promoters, enhancers, and insulator regions, leading to transcriptional deregulation, G2/M cell-cycle arrest, chromosome aneuploidy, and aberrations. In support of these observations, knocking down the expression of H3.3 induced cell transformation, whereas ectopic expression of H3.3 attenuated arsenic-induced cell transformation. Notably, arsenic exposure also resulted in displacement of H3.3 from active promoters, enhancers, and insulator regions. These data suggest that H3.3 displacement might be central to carcinogenesis caused by polyadenylation of H3.1 mRNA upon arsenic exposure. Our findings illustrate the importance of proper histone stoichiometry in maintaining genome integrity. [Display omitted] •Arsenic induces polyadenylation of canonical histone H3.1 mRNA in vivo•Polyadenylation of H3.1 mRNA promotes tumor formation in nude mice•The variant H3.3 is displaced from regulatory elements by polyadenylated H3.1 mRNA•Polyadenylated H3.1 mRNA causes abnormal transcription and chromosomal instability Toxicology; Cell Biology; Omics
Bibliography:Lead Contact
Present address: Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Medical College, Wuhan University of Science and Technology, Wuhan 430081, China
Present address: Chemistry and Biomedicine Innovation Center, Medical School of Nanjing University, Nanjing 210093, China
Present address: Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
These authors contributed equally
Present address: Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710049, China
Present address: Institute of Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA
Present address: Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX 77843, USA
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.101518