Inorganic Arsenic-induced cellular transformation is coupled with genome wide changes in chromatin structure, transcriptome and splicing patterns

BMC Genomics

Yvonne N Fondufe-Mittendorf¹  Eric C Rouchka³  Kuey Chu Chen²  Zhou Zhang⁴  Steven Grason Godfrey¹  Manana Melikishvili¹  Ye Ma¹  Caitlyn Riedmann¹ 

[1]Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington 40536, KY, USA

[2]Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington 40536, KY, USA

[3]Department of Computer Engineering and Computer Science, University of Louisville, Louisville 40292, KY, USA

[4]Graduate Center for Toxicology, University of Kentucky, Lexington 40536, KY, USA

关键词: Splicing;    Arsenic;    Chromatin;    Genome-wide;    Gene expression;   

Others  :  1140492
DOI  :  10.1186/s12864-015-1295-9

 received in 2014-09-02, accepted in 2015-01-29,  发布年份 2015

【 摘 要 】

Background

Arsenic (As) exposure is a significant worldwide environmental health concern. Low dose, chronic arsenic exposure has been associated with a higher than normal risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. While arsenic-induced biological changes play a role in disease pathology, little is known about the dynamic cellular changes resulting from arsenic exposure and withdrawal.

Results

In these studies, we sought to understand the molecular mechanisms behind the biological changes induced by arsenic exposure. A comprehensive global approach was employed to determine genome-wide changes to chromatin structure, transcriptome patterns and splicing patterns in response to chronic low dose arsenic and its subsequent withdrawal. Our results show that cells exposed to chronic low doses of sodium arsenite have distinct temporal and coordinated chromatin, gene expression, and miRNA changes consistent with differentiation and activation of multiple biochemical pathways. Most of these temporal patterns in gene expression are reversed when arsenic is withdrawn. However, some gene expression patterns remained altered, plausibly as a result of an adaptive response by cells. Additionally, the correlation of changes to gene expression and chromatin structure solidify the role of chromatin structure in gene regulatory changes due to arsenite exposure. Lastly, we show that arsenite exposure influences gene regulation both at the initiation of transcription as well as at the level of splicing.

Conclusions

Our results show that adaptation of cells to iAs-mediated EMT is coupled to changes in chromatin structure effecting differential transcriptional and splicing patterns of genes. These studies provide new insights into the mechanism of iAs-mediated pathology, which includes epigenetic chromatin changes coupled with changes to the transcriptome and splicing patterns of key genes.

【 授权许可】

   
2015 Riedmann et al.; licensee BioMed Central.

【 图 表 】

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