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

60 Pages Posted: 21 Nov 2019 Publication Status: Review Complete

See all articles by Danqi Chen

Danqi Chen

New York University (NYU) - Department of Environmental Medicine

Qiao Yi Chen

New York University (NYU) - Department of Environmental Medicine

Zhenjia Wang

University of Virginia - Center for Public Health Genomics

Yusha Zhu

New York University (NYU) - Department of Environmental Medicine

Thomas Kluz

New York University (NYU) - Department of Environmental Medicine

Wuwei Tan

University of Virginia - Center for Public Health Genomics

Jinquan Li

New York University (NYU) - Department of Environmental Medicine

Feng Wu

New York University (NYU) - Department of Environmental Medicine

Lei Fang

New York University (NYU) - Department of Environmental Medicine

Xiaoru Zhang

New York University (NYU) - Department of Environmental Medicine

Rongquan He

University of Virginia - Center for Public Health Genomics

Steven Shen

New York University (NYU) - Department of Environmental Medicine

Hong Sun

New York University (NYU) - Department of Environmental Medicine

Chongzhi Zang

University of Virginia - Center for Public Health Genomics

Chunyuan Jin

New York University (NYU) - Department of Environmental Medicine

Max Costa

New York University (NYU) - Department of Environmental Medicine

More...

Abstract

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. The addition of a poly(A) tail to the H3.1 mRNA caused transformation of human cells in vitro, but the underlying mechanisms are unknown. Here we report that polyadenylation of H3.1 mRNA increases H3.1 protein level, resulting in depletion of histone variant H3.3 at active promoters, enhancers, and insulator regions through its displacement. Cells underwent transcriptional deregulation, G2/M cell cycle arrest, chromosome aneuploidy and aberrations. Furthermore, knocking down the expression of H3.3 induced cell transformation, whereas ectopic expression of H3.3 attenuated arsenic-induced cell transformation, suggesting that H3.3 displacement might be central to tumorigenic effects of polyadenylated H3.1 mRNA. Our study provides novel insights into the importance of proper histone stoichiometry in maintaining genome integrity.

Keywords: Canonical histones, Histone variants, H3.1, H3.3, polyadenylation, arsenic, transcription, carcinogenesis

Suggested Citation

Chen, Danqi and Chen, Qiao Yi and Wang, Zhenjia and Zhu, Yusha and Kluz, Thomas and Tan, Wuwei and Li, Jinquan and Wu, Feng and Fang, Lei and Zhang, Xiaoru and He, Rongquan and Shen, Steven and Sun, Hong and Zang, Chongzhi and Jin, Chunyuan and Costa, Max, Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements (November 19, 2019). Available at SSRN: https://ssrn.com/abstract=3490279 or http://dx.doi.org/10.2139/ssrn.3490279
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Danqi Chen

New York University (NYU) - Department of Environmental Medicine ( email )

United States

Qiao Yi Chen

New York University (NYU) - Department of Environmental Medicine ( email )

United States

Zhenjia Wang

University of Virginia - Center for Public Health Genomics ( email )

United States

Yusha Zhu

New York University (NYU) - Department of Environmental Medicine ( email )

United States

Thomas Kluz

New York University (NYU) - Department of Environmental Medicine ( email )

United States

Wuwei Tan

University of Virginia - Center for Public Health Genomics ( email )

United States

Jinquan Li

New York University (NYU) - Department of Environmental Medicine ( email )

United States

Feng Wu

New York University (NYU) - Department of Environmental Medicine

United States

Lei Fang

New York University (NYU) - Department of Environmental Medicine

United States

Xiaoru Zhang

New York University (NYU) - Department of Environmental Medicine ( email )

United States

Rongquan He

University of Virginia - Center for Public Health Genomics ( email )

United States

Steven Shen

New York University (NYU) - Department of Environmental Medicine

United States

Hong Sun

New York University (NYU) - Department of Environmental Medicine

United States

Chongzhi Zang

University of Virginia - Center for Public Health Genomics ( email )

United States

Chunyuan Jin (Contact Author)

New York University (NYU) - Department of Environmental Medicine ( email )

United States

Max Costa

New York University (NYU) - Department of Environmental Medicine

United States

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