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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Article number101518
JournaliScience
Volume23
Issue number9
DOIs
StatePublished - Sep 25 2020
Externally publishedYes

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

PubMed: MeSH publication types

  • Journal Article

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