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

doi:10.1016/j.isci.2020.101518

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

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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, 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.

Original language	English (US)
Article number	101518
Journal	iScience
Volume	23
Issue number	9
DOIs	https://doi.org/10.1016/j.isci.2020.101518
State	Published - Sep 25 2020
Externally published	Yes

Bibliographical note

Funding Information:
We thank the NYULMC Genome Technology Center, partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. The authors thank Drs. Sitharam Ramaswami, Thomas Des Marais and Gabriele Grunig for technical assistance and Suresh Cuddapah for helpful comments. The graphic abstract was created with BioRender.com. This work was supported by grants from the US National Institutes of Health : R01ES026138 (M.C. and C.J.), P30ES000260 (M.C. and Pilot Project Program to C.J.), R01ES029359 (M.C. and C.J.), R01ES030583 (C.J. and M.C.), R01ES022935 (M.C.), R35GM133712 (C.Z.), and K22CA204439 (C.Z.).

Publisher Copyright:
© 2020 The Author(s)

Keywords

Cell Biology
Omics
Toxicology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2020.101518

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

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, 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.",

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AU - Chen, Danqi

AU - Chen, Qiao Yi

AU - Wang, Zhenjia

AU - Zhu, Yusha

AU - Kluz, Thomas

AU - Tan, Wuwei

AU - Li, Jinquan

AU - Wu, Feng

AU - Fang, Lei

AU - Zhang, Xiaoru

AU - He, Rongquan

AU - Shen, Steven

AU - Sun, Hong

AU - Zang, Chongzhi

AU - Jin, Chunyuan

AU - Costa, Max

N1 - Funding Information: We thank the NYULMC Genome Technology Center, partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. The authors thank Drs. Sitharam Ramaswami, Thomas Des Marais and Gabriele Grunig for technical assistance and Suresh Cuddapah for helpful comments. The graphic abstract was created with BioRender.com. This work was supported by grants from the US National Institutes of Health : R01ES026138 (M.C. and C.J.), P30ES000260 (M.C. and Pilot Project Program to C.J.), R01ES029359 (M.C. and C.J.), R01ES030583 (C.J. and M.C.), R01ES022935 (M.C.), R35GM133712 (C.Z.), and K22CA204439 (C.Z.). Publisher Copyright: © 2020 The Author(s)

PY - 2020/9/25

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N2 - 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.

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KW - Omics

KW - Toxicology

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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