Abstract
Gene expression is a dynamic and coordinated process coupling transcription with pre-mRNA processing. This regulation enables tissue-specific transcription factors to induce expression of specific transcripts that are subsequently amplified by alternative splicing allowing for increased proteome complexity and functional diversity. The intestine-specific transcription factor CDX2 regulates development and maintenance of the intestinal epithelium by inducing expression of genes characteristic of the mature enterocyte phenotype. Here, sequence analysis of CDX2 mRNA from colonic mucosa-derived tissues revealed an alternatively spliced transcript (CDX2/AS) that encodes a protein with a truncated homeodomain and a novel carboxy-terminal domain enriched in serine and arginine residues (RS domain). CDX2 and CDX2/AS exhibited distinct nuclear expression patterns with minimal areas of co-localization. CDX2/AS did not activate the CDX2-dependent promoter of guanylyl cyclase C nor inhibit transcriptional activity of CDX2. Unlike CDX2, CDX2/AS co-localized with the putative splicing factors ASF/SF2 and SC35. CDX2/AS altered splicing patterns of CD44v5 and Tra2-β1 minigenes in Lovo colon cancer cells independent of CDX2 expression. These data demonstrate unique dual functions of the CDX2 gene enabling it to regulate gene expression through both transcription (CDX2) and pre-mRNA processing (CDX2/AS).
Highlights
Gene expression is a highly dynamic and efficient process that couples transcription with pre-mRNA processing [1]
We attributed the generation of CDX2 transcript (CDX2/AS) to alternative splicing in which the non-canonical 59 splice donor sequence, GC, located at the distal segment of exon 2 is utilized rather than the wild type GU donor sequence of intron 2 (Fig. 1B)
The alternative splicinginduced frameshift occurs in the distal region of the homeobox binding domain and encodes a protein in which the 85 carboxyl terminal residues in the wild type protein are replaced with a novel residue domain enriched in serine and arginine amino acids (Fig. 1C)
Summary
Gene expression is a highly dynamic and efficient process that couples transcription with pre-mRNA processing [1]. Regulation of transcription occurs through DNA modifications and changes in transcription factor expression, activity, and localization. In addition to these generalized processes, transcription factor expression and activity is subjected to tissue-specific mechanisms of regulation [4,5,6]. This process enables expression of restricted sets of tissue-specific transcripts [4,5,6]. These transcripts are processed by ubiquitously expressed splicing factors to generate alternative transcripts, thereby increasing proteome complexity and ensuring functional diversity
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