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Unusual misregulation of RNA splicing caused by insertion of a transposable element into the T (Brachyury) locus.

ABSTRACT: BACKGROUND:The TWis mutant allele of the Brachyury, or T, gene was created by insertion of an endogenous retrovirus-like early transposon (ETn) element into the exon 7 splice donor consensus sequence of the 8 exon T locus. While the developmental consequences of this disruption have been well characterized, the molecular consequences have not been previously investigated, and it has been assumed that the insertion results in a truncated protein. This study sought to further characterize the mutant TWis allele by investigating the nature of the transcripts produced by insertion of this transposable element. RESULTS:Using an RT-PCR based approach, we have shown that at least 8 different mutant transcripts are produced from the TWis allele. All TWis transcripts bypass the mutated exon 7 splice donor site, such that wild type T transcripts are not produced from the TWis allele. CONCLUSIONS:This result shows an unsuspected misregulation of RNA splicing caused by insertion of a transposable element, that could have more widespread consequences in the genome.

SUBMITTER: Goldin SN

PROVIDER: S-EPMC155784 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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Unusual misregulation of RNA splicing caused by insertion of a transposable element into the T (Brachyury) locus.

Goldin Sarah N SN Papaioannou Virginia E VE

BMC genomics 20030417 1

<h4>Background</h4>The TWis mutant allele of the Brachyury, or T, gene was created by insertion of an endogenous retrovirus-like early transposon (ETn) element into the exon 7 splice donor consensus sequence of the 8 exon T locus. While the developmental consequences of this disruption have been well characterized, the molecular consequences have not been previously investigated, and it has been assumed that the insertion results in a truncated protein. This study sought to further characterize ...[more]

PMID: 12702217

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Project description:Human transposable element (TE) activity in somatic tissues causes mutations that can contribute to tumorigenesis. Indeed, TE insertion mutations have been implicated in the etiology of a number of different cancer types. Nevertheless, the full extent of somatic TE activity, along with its relationship to tumorigenesis, have yet to be fully explored. Recent developments in bioinformatics software make it possible to analyze TE expression levels and TE insertional activity directly from transcriptome (RNA-seq) and whole genome (DNA-seq) next-generation sequence data. We applied these new sequence analysis techniques to matched normal and primary tumor patient samples from the Cancer Genome Atlas (TCGA) in order to analyze the patterns of TE expression and insertion for three cancer types: breast invasive carcinoma, head and neck squamous cell carcinoma, and lung adenocarcinoma. Our analysis focused on the three most abundant families of active human TEs: Alu, SVA, and L1. We found evidence for high levels of somatic TE activity for these three families in normal and cancer samples across diverse tissue types. Abundant transcripts for all three TE families were detected in both normal and cancer tissues along with an average of ~80 unique TE insertions per individual patient/tissue. We observed an increase in L1 transcript expression and L1 insertional activity in primary tumor samples for all three cancer types. Tumor-specific TE insertions are enriched for private mutations, consistent with a potentially causal role in tumorigenesis. We used genome feature analysis to investigate two specific cases of putative cancer-causing TE mutations in further detail. An Alu insertion in an upstream enhancer of the CBL tumor suppressor gene is associated with down-regulation of the gene in a single breast cancer patient, and an L1 insertion in the first exon of the BAALC gene also disrupts its expression in head and neck squamous cell carcinoma. Our results are consistent with widespread somatic activity of human TEs leading to numerous insertion mutations that can contribute to tumorigenesis in a variety of tissues.

Dataset Information

Unusual misregulation of RNA splicing caused by insertion of a transposable element into the T (Brachyury) locus.

Publications

Unusual misregulation of RNA splicing caused by insertion of a transposable element into the T (Brachyury) locus.

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