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

被引：17

作者：

Chen, Danqi ^{[1
]}

Chen, Qiao Yi ^{[1
,7
]}

Wang, Zhenjia ^{[4
]}

Zhu, Yusha ^{[1
]}

Kluz, Thomas ^{[1
]}

Tan, Wuwei ^{[4
,5
,12
]}

Li, Jinquan ^{[1
,8
]}

Wu, Feng ^{[1
]}

Fang, Lei ^{[1
,9
]}

Zhang, Xiaoru ^{[1
]}

He, Rongquan ^{[4
,10
]}

Shen, Steven ^{[1
,11
]}

Sun, Hong ^{[1
]}

Zang, Chongzhi ^{[4
,6
]}

Jin, Chunyuan ^{[1
,3
]}

Costa, Max ^{[1
,2
]}

机构：

[1] NYU, Sch Med, Dept Environm Med, New York, NY 10010 USA

[2] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA

[3] NYU Langone Hlth, Perlmutter Canc Ctr, New York, NY 10016 USA

[4] Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA

[5] Univ Virginia, Dept Stat, Charlottesville, VA 22904 USA

[6] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA

[7] Xi An Jiao Tong Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Cell Biol & Genet, Xian 710049, Peoples R China

[8] Wuhan Univ Sci & Technol, Med Coll, Hubei Prov Key Lab Occupat Hazard Identificat & C, Wuhan 430081, Peoples R China

[9] Nanjing Univ, Med Sch, Chem & Biomed Innovat Ctr, Nanjing 210093, Peoples R China

[10] Guangxi Med Univ, Affiliated Hosp 1, Dept Med Oncol, Nanning 530021, Peoples R China

[11] Univ Minnesota, Inst Hlth Informat, Minneapolis, MN 55455 USA

[12] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA

来源：

ISCIENCE | 2020年 / 23卷 / 09期

基金：

美国国家卫生研究院;

关键词：

LOOP-BINDING-PROTEIN; VARIANT H3.3; ARSENIC EXPOSURE; DRINKING-WATER; 3' END; MUTATIONS; CYCLE; TRANSCRIPTION; CANCER; LUNG;

D O I：

10.1016/j.isci.2020.101518

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Replication-dependent canonical histone messenger RNAs (mRNAs) do not terminate with a poly(A) tail at the 30 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.

引用

页数：35

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