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

iScience

Max Costa¹  Jinquan Li²  Zhenjia Wang³  Steven Shen³  Wuwei Tan³  Chunyuan Jin³  Qiao Yi Chen⁴  Danqi Chen⁴  Yusha Zhu⁴  Thomas Kluz⁴  Feng Wu⁴  Chongzhi Zang⁴  Xiaoru Zhang⁴  Hong Sun⁴  Lei Fang⁴  Rongquan He⁴ 

[1] Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA;Department of Statistics, University of Virginia, Charlottesville, VA 22904, USA;Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA;Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA;

关键词: Toxicology;    Cell Biology;    Omics;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown