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Global Analysis of Post-transcriptional Gene Expression in Arsenite-treated Human BJ Fibroblasts

ABSTRACT: Arsenic is a potent environmental toxin and a cause of numerous health problems. Most studies have assumed that arsenic-induced changes in mRNA levels result from effects on gene transcription. The influence of arsenic on post-transcriptional regulation, another important locus of gene expression control, has remained largely unexplored. To evaluate the prevalence of changes in mRNA stability in response to arsenic in human fibroblasts, we used microarray analyses to determine changes in steady state mRNA levels, and their decay rates, following 24 hour exposure to non-cytotoxic concentrations of sodium arsenite (1 µM). We conclude that arsenite modification of mRNA stability is relatively uncommon, but in some instances can result in significant changes in gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57051 | GEO | 2015/04/15

SECONDARY ACCESSION(S): PRJNA245323

REPOSITORIES: GEO

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Project description:Arsenic (As) exposure is a significant worldwide environmental health concern. Low dose, chronic arsenic exposure has been associated with higher 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 due to arsenic exposure and withdrawal. In these studies, we seek to understand the molecular mechanisms behind the biological changes induced by chronic low doses of arsenic exposure. We used a comprehensive approach involving chromatin structural studies and mRNA microarray analyses to determine how chromatin structure and gene expression patterns change in response to chronic low dose arsenic exposure and its subsequent withdrawal. Our results show that cells exposed to low doses of sodium arsenite have distinct temporal and coordinated chromatin, gene expression and miRNA changes that are consistent with differentiation and activation of multiple biochemical pathways. Most of these temporal patterns in gene expression are reversed when arsenic was withdrawn. However, some of the gene expression patterns remained altered, plausibly as a result of an adaptive response by these cells. Additionally, these gene expression patterns correlated with changes in chromatin structure, further solidifying 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 transcription initiation as well as at the splicing level. Thus our results suggest that general patterns of alternative splicing, as well as expression of particular gene regulators, can be indicative of arsenite-induced cell transformation. A total of eight (8) samples with two biological replicates under four separate conditions: wild-type treated with deionized H2O for 36 days (NT); chronic low-dose arsenic exposure of 1 uM of sodium arsenite (iAs-T) for 36 days; chronic arsenic exposure of 1 uM of sodium arsenite for 26 days followed by removal of sodium arsenite for 10 days, measured at day 36 (iAs-Rev); and chronic arsenic exposure of 1 uM of sodium arsenite for 26 days, followed by removal of sodium arsenite exposure for 10 days, followed by 1 uM of chronic sodium arsenite exposure for 10 days (measured at day 46) (iAs-Rev-T).

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Global Analysis of Post-transcriptional Gene Expression in Arsenite-treated Human BJ Fibroblasts

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