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

Caitlyn Riedmann, Ye Ma, Manana Melikishvili, Steven Grason Godfrey, Zhou Zhang, Kuey Chu Chen, Eric C. Rouchka, Yvonne N. Fondufe-Mittendorf

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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 Most of these temporal patterns in gene expression are reversed when arsenic is withdrawn.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.

Original languageEnglish
Article number212
JournalBMC Genomics
Volume16
Issue number1
DOIs
StatePublished - Mar 19 2015

Bibliographical note

Funding Information:
YNF-M conceived the study and designed the experiments. CR, YM, MM, SGG, and YNF-M performed all experiments; KCC, ER, YNF-M performed computational analyses; YNF-M supervised the experimental and/or statistical analyses, ZZ provided conceptual insights, and CR, YM, MM, ZZ, KCC, ER, YNF-M wrote the manuscript. All authors read and approved the final manuscript. This research was supported by NIH grant P20GM103436 to ER and grants 2P20 RR020171 and International Rett Syndrome Foundation to YNF-M.

Publisher Copyright:
© Riedmann et al.; licensee BioMed Central.

Keywords

  • Arsenic
  • Chromatin
  • Gene expression
  • Genome-wide
  • Splicing

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

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