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Extensive Alternative Splicing of the Repressor Element Silencing Transcription Factor Linked to Cancer
- Source :
- PLoS ONE, PLoS ONE, Vol 8, Iss 4, p e62217 (2013)
- Publication Year :
- 2013
- Publisher :
- Public Library of Science (PLoS), 2013.
-
Abstract
- The repressor element silencing transcription factor (REST) is a coordinate transcriptional and epigenetic regulator which functions as a tumor suppressor or an oncogene depending on cellular context, and a truncated splice variant REST4 has been linked to various types of cancer. We performed a comprehensive analysis of alternative splicing (AS) of REST by rapid amplification of cDNA ends and PCR amplification of cDNAs from various tissues and cell lines with specific primers. We identified 8 novel alternative exons including an alternate last exon which doubles the REST gene boundary, along with numerous 5'/3' splice sites and ends in the constitutive exons. With the combination of various splicing patterns (e.g. exon skipping and alternative usage of the first and last exons) that are predictive of altered REST activity, at least 45 alternatively spliced variants of coding and non-coding mRNA were expressed in a species- and cell-type/tissue-specific manner with individual differences. By examining the repertoire of REST pre-mRNA splicing in 27 patients with kidney, liver and lung cancer, we found that all patients without exception showed differential expression of various REST splice variants between paired tumor and adjacent normal tissues, with striking cell-type/tissue and individual differences. Moreover, we revealed that exon 3 skipping, which causes no frame shift but loss of a domain essential for nuclear translocation, was affected by pioglitazone, a highly selective activator of the peroxisome proliferator-activated receptor gamma (PPARĪ³) which contributes to cell differentiation and tumorigenesis besides its metabolic actions. Accordingly, this study demonstrates an extensive AS of REST pre-mRNA which redefines REST gene boundary and structure, along with a general but differential link between REST pre-mRNA splicing and various types of cancer. These findings advance our understanding of the complex, context-dependent regulation of REST gene expression and function, and provide potential biomarkers and therapeutic targets for cancer.
- Subjects :
- Epidemiology
lcsh:Medicine
Biochemistry
Gene Splicing
Exon
Molecular cell biology
0302 clinical medicine
Rapid amplification of cDNA ends
Neoplasms
Basic Cancer Research
Gene expression
lcsh:Science
Genetics
Regulation of gene expression
0303 health sciences
Multidisciplinary
Cancer Risk Factors
Physics
Exons
3. Good health
Cell biology
Nucleic acids
Oncology
RNA splicing
Medicine
Epigenetics
Research Article
Genetic Causes of Cancer
Biophysics
Biology
Molecular Genetics
03 medical and health sciences
Cancer Genetics
Humans
Gene Regulation
Gene
030304 developmental biology
lcsh:R
Alternative splicing
Computational Biology
Exon skipping
Repressor Proteins
Biomarker Epidemiology
Alternative Splicing
RNA processing
RNA
lcsh:Q
030217 neurology & neurosurgery
Transcription Factors
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....7712198a4d9c6340c371d2ad7071a89f