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

Chen, D.; Chen, Q. Y.; Wang, Z.; Zhu, Y.; Kluz, T.; Tan, W.; Li, J.; Wu, F.; Fang, L.; Zhang, X.; He, R.; Shen, S.; Sun, H.; Zang, C.; Jin, C.; Costa, M.

doi:10.1101/806828

bioRxiv · 10.1101/806828

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

Chen, D.·Chen, Q. Y.·Wang, Z.·Zhu, Y.·Kluz, T.·Tan, W.·Li, J.·Wu, F.·Fang, L.·Zhang, X.·He, R.·Shen, S.·Sun, H.·Zang, C.·Jin, C.·Costa, M.

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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. 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.\n\nHighlightsO_LIPolyadenylation of canonical histone H3.1 mRNA promotes tumor formation in nude mice\nC_LIO_LIHistone variant H3.3 is displaced from critical gene regulatory elements by overexpression of polyadenylated H3.1 mRNA\nC_LIO_LIIncreased polyadenylated H3.1 mRNA causes abnormal transcription, cell cycle arrest, and chromosomal instability\nC_LIO_LIArsenic induces polyadenylation of H3.1 mRNA in vivo\nC_LI

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Chen, D., Chen, Q. Y., Wang, Z., Zhu, Y., Kluz, T., Tan, W., Li, J., Wu, F., Fang, L., Zhang, X., He, R., Shen, S., Sun, H., Zang, C., Jin, C., Costa, M.. 2019-10-16. Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements. https://doi.org/10.1101/806828

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