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Your Environment. Your Health.

ALTERNATIVE SPLICING IN ARSENICAL SKIN CARCINOGENESIS

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/R21ES030334/format/word)
Principal Investigator: States, J Christopher
Institute Receiving Award University Of Louisville
Location Louisville, KY
Grant Number R21ES030334
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 14 Jul 2020 to 30 Jun 2022
DESCRIPTION (provided by applicant): Project Summary Chronic exposure to arsenic, most commonly through contaminated drinking water, plagues over 200 million individuals in over 70 countries including the USA. Arsenic is a multi-organ toxicant and chronic arsenic exposure causes several chronic diseases including cancer in multiple organs, skin cancer being the most common. While several mechanisms are postulated to be responsible for arsenic-induced carcinogenesis, a clear picture is yet to emerge. It is well known that chronic arsenic exposure radically changes the transcriptomic and proteomic signatures, but the underlying mechanism for such sweeping global changes are not yet clearly understood. Differential alternative splicing plays a role in carcinogenesis and may be at play in arsenic-induced carcinogenesis. We employed state-of-the-art RNA-Seq analysis in a well-established model of arsenic-induced skin cancer (HaCaT cells exposed continuously to 100 nM sodium arsenite for 32 weeks) in a longitudinal study to understand the global changes in splicing occurring during the transformation process. Our data indicate >600 differential alternative splicing events occurred at each of the time points studied (7, 19, 28 weeks of exposure). This differential splicing program, by dramatically changing the proteome, could be a key player in the arsenic-induced transformation of skin cells. The present proposal aims to examine the contribution of significant differential splicing events at each time point towards the process of carcinogenesis. We will specifically scrutinize if the significant splicing events predicted by our transcriptomic studies can be correlated with protein isoform expression profiles. Furthermore, we also aim to study if predicted significantly different spliced isoforms that take place in the 5' or 3' UTR of transcripts can be correlated to expression profile in the mature mRNA samples from exposed and unexposed cells. The outcomes from this study will further our understanding of how alternative splicing shapes the cellular events taking place before, during and after the time the HaCaT cells become malignant. In addition, our study will look to elaborate the mechanistic basis of how one change in an upstream regulatory alternative splicing factor can cause genome-wide synchronized alternative splicing changes by signal amplification through successive steps, leading to altered proteome and ultimately adverse health effects.
Science Code(s)/Area of Science(s) Primary: 58 - Skin
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Michael Humble
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