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Alternative splicing of T-box transcription factor genes.

ABSTRACT: T-box (TBX) transcription factors are an ancient gene family with critical roles in embryogenesis. Currently, TBX3, TBX5, and TBX20 are TBX genes defined to have multiple protein isoforms created by alternative splicing and characterized by expression and functional studies. These proteins are important for development as mutations lead to severe developmental disorders in humans and mice. Cumulative studies suggest that alternative splicing of these genes can regulate TBX activities during multiple biological processes including cardiogenesis, limb development, and cancer mechanisms. This mini-review focuses on how alternative splicing adds complexity to transcriptional regulation of target genes controlled by TBX transcription factors.

SUBMITTER: DeBenedittis P

PROVIDER: S-EPMC3171624 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Alternative splicing of T-box transcription factor genes.

DeBenedittis Paige P Jiao Kai K

Biochemical and biophysical research communications 20110811 4

T-box (TBX) transcription factors are an ancient gene family with critical roles in embryogenesis. Currently, TBX3, TBX5, and TBX20 are TBX genes defined to have multiple protein isoforms created by alternative splicing and characterized by expression and functional studies. These proteins are important for development as mutations lead to severe developmental disorders in humans and mice. Cumulative studies suggest that alternative splicing of these genes can regulate TBX activities during mult ...[more]

PMID: 21856288

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Project description: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 (PPAR?) 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.

Dataset Information

Alternative splicing of T-box transcription factor genes.

Publications

Alternative splicing of T-box transcription factor genes.

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