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  RNA-Seq provides new insights in the transcriptome responses induced by the carcinogen benzo[a]pyrene

van Delft, J., Gaj, S., Lienhard, M., Albrecht, M., Kirpiy, A., Brauers, K., et al. (2012). RNA-Seq provides new insights in the transcriptome responses induced by the carcinogen benzo[a]pyrene. Toxicological Sciences, 130(2), 427-439. doi:10.1093/toxsci/kfs250.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F0AF-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F0B0-E
Genre: Journal Article

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 Creators:
van Delft, Joost, Author
Gaj, Stan, Author
Lienhard, Matthias1, Author              
Albrecht, Markus1, Author              
Kirpiy, Alexander2, Author              
Brauers, Karen, Author
Claessen, Sandra, Author
Lizarraga, Daneida, Author
Lehrach, Hans2, Author              
Herwig, Ralf1, Author              
Kleinjans, Jos, Author
Affiliations:
1Bioinformatics (Ralf Herwig), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479648              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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 Abstract: Whole-genome transcriptome measurements are pivotal for characterizing molecular mechanisms of chemicals and predicting toxic classes, such as genotoxicity and carcinogenicity, from in vitro and in vivo assays. In recent years, deep sequencing technologies have been developed that hold the promise of measuring the transcriptome in a more complete and unbiased manner than DNA microarrays. Here, we applied this RNA-seq technology for the characterization of the transcriptomic responses in HepG2 cells upon exposure to benzo[a]pyrene (BaP), a well-known DNA damaging human carcinogen. Based on EnsEMBL genes, we demonstrate that RNA-seq detects ca 20% more genes than microarray-based technology but almost threefold more significantly differentially expressed genes. Functional enrichment analyses show that RNA-seq yields more insight into the biology and mechanisms related to the toxic effects caused by BaP, i.e., two- to fivefold more affected pathways and biological processes. Additionally, we demonstrate that RNA-seq allows detecting alternative isoform expression in many genes, including regulators of cell death and DNA repair such as TP53, BCL2 and XPA, which are relevant for genotoxic responses. Moreover, potentially novel isoforms were found, such as fragments of known transcripts, transcripts with additional exons, intron retention or exon-skipping events. The biological function(s) of these isoforms remain for the time being unknown. Finally, we demonstrate that RNA-seq enables the investigation of allele-specific gene expression, although no changes could be observed. Our results provide evidence that RNA-seq is a powerful tool for toxicology, which, compared with microarrays, is capable of generating novel and valuable information at the transcriptome level for characterizing deleterious effects caused by chemicals.

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Language(s): eng - English
 Dates: 2012-08-132012-12
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1093/toxsci/kfs250
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Title: Toxicological Sciences
Source Genre: Journal
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Publ. Info: Oxford University Press
Pages: - Volume / Issue: 130 (2) Sequence Number: - Start / End Page: 427 - 439 Identifier: -