Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements
Danqi Chen,
Qiao Yi Chen,
Zhenjia Wang,
Yusha Zhu,
Thomas Kluz,
Wuwei Tan,
Jinquan Li,
Feng Wu,
Lei Fang,
Xiaoru Zhang,
Rongquan He,
Steven Shen,
Hong Sun,
Chongzhi Zang,
Chunyuan Jin,
Max Costa
Affiliations
Danqi Chen
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Qiao Yi Chen
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Zhenjia Wang
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Yusha Zhu
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Thomas Kluz
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Wuwei Tan
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Statistics, University of Virginia, Charlottesville, VA 22904, USA
Jinquan Li
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Feng Wu
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Lei Fang
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Xiaoru Zhang
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Rongquan He
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Steven Shen
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Hong Sun
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
Chongzhi Zang
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA; Corresponding author
Chunyuan Jin
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA; Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA; Corresponding author
Max Costa
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA; Corresponding author
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.
