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Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts
Published on: October 9, 2016
Entropy measures quantify global splicing disorders in cancer
William Ritchie1, Samuel Granjeaud, Denis Puthier
1Université de Méditerranée, INSERM ERM 206, Technologies Avancées pour le Génome et Clinique, Marseille, France.
Abstract:
Most mammalian genes are able to express several splice variants in a phenomenon known as alternative splicing. Serious alterations of alternative splicing occur in cancer tissues, leading to expression of multiple aberrant splice forms. Most studies of alternative splicing defects have focused on the identification of cancer-specific splice variants as potential therapeutic targets. Here, we examine instead the bulk of non-specific transcript isoforms and analyze their level of disorder using a measure of uncertainty called Shannon's entropy. We compare isoform expression entropy in normal and cancer tissues from the same anatomical site for different classes of transcript variations: alternative splicing, polyadenylation, and transcription initiation. Whereas alternative initiation and polyadenylation show no significant gain or loss of entropy between normal and cancer tissues, alternative splicing shows highly significant entropy gains for 13 of the 27 cancers studied. This entropy gain is characterized by a flattening in the expression profile of normal isoforms and is correlated to the level of estimated cellular proliferation in the cancer tissue. Interestingly, the genes that present the highest entropy gain are enriched in splicing factors. We provide here the first quantitative estimate of splicing disruption in cancer. The expression of normal splice variants is widely and significantly disrupted in at least half of the cancers studied. We postulate that such splicing disorders may develop in part from splicing alteration in key splice factors, which in turn significantly impact multiple target genes.
Insights
Cancer tissues exhibit significant disruptions in normal alternative splicing, leading to increased disorder in gene expression. This splicing dysregulation, measured by Shannon
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- Alternative splicing is a fundamental process in mammalian gene expression, producing multiple transcript variants from a single gene.
- Cancer is characterized by significant alterations in alternative splicing, often leading to aberrant splice forms.
- Previous research has focused on identifying cancer-specific splice variants, overlooking broader changes in normal isoform expression.
Purpose of the Study:
- To quantitatively assess the disruption of normal splice variant expression in cancer tissues.
- To compare the level of disorder (Shannon's entropy) in alternative splicing, polyadenylation, and transcription initiation between normal and cancer tissues.
- To investigate the relationship between splicing disruption, cellular proliferation, and the expression of splicing factors in cancer.
Main Methods:
- Analysis of isoform expression profiles in normal and cancer tissues from the same anatomical sites.
- Quantification of expression disorder using Shannon's entropy for different transcript variation types.
- Correlation analysis between splicing entropy gain, cellular proliferation estimates, and the abundance of splicing factor genes.
Main Results:
- Alternative splicing, but not polyadenylation or transcription initiation, showed significant entropy gains in 13 of 27 studied cancers.
- This gain in splicing entropy reflects a flattening of normal isoform expression profiles and correlates with increased cellular proliferation.
- Genes exhibiting the highest splicing entropy gain are enriched in splicing factors, suggesting a feedback mechanism.
Conclusions:
- The expression of normal splice variants is significantly disrupted in at least half of the studied cancers, representing a major splicing disorder.
- Splicing disruptions may arise from alterations in key splicing factors, which subsequently impact multiple target genes.
- This study provides the first quantitative estimate of splicing disruption in cancer, highlighting its prevalence and potential mechanisms.
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