Alternative splicing of Tcf7l2 transcripts generates protein variants with differential promoter-binding and transcriptional activation properties at Wnt/β-catenin targets

• Published in: Nucleic acids research Vol. 38; no. 6; pp. 1964 - 1981
• Main Authors: Weise, Andreas, Bruser, Katja, Elfert, Susanne, Wallmen, Britta, Wittel, Yvonne, Wöhrle, Simon, Hecht, Andreas
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2010
• Subjects: Alternative Splicing; Amino Acid Sequence; Animals; beta Catenin - metabolism; Cell Line; complement; DNA; DNA-binding domains; DNA-binding proteins; embryonic stem cells; exons; Genetic Variation; Humans; Mice; Molecular Biology; molecular cloning; Molecular Sequence Data; polymerase chain reaction; Promoter Regions, Genetic; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; protein products; sequence analysis; T-lymphocytes; TCF Transcription Factors - chemistry; TCF Transcription Factors - genetics; TCF Transcription Factors - metabolism; Tissue Distribution; tissues; transcription (genetics); Transcription Factor 7-Like 2 Protein; Transcriptional Activation; Wnt Proteins - pharmacology
• DOI: 10.1093/nar/gkp1197
• ISSN: 0305-1048; 1362-4962

Alternative splicing can produce multiple protein products with variable domain composition from a single gene. The mouse Tcf7l2 gene is subject to alternative splicing. It encodes TCF4, a member of the T-cell factor (TCF) family of DNA-binding proteins and a nuclear interaction partner of β-catenin which performs essential functions in Wnt growth factor signalling. Multiple TCF4 isoforms, potentially exhibiting cell-type-specific distribution and differing in gene regulatory properties, could strongly influence tissue-specific Wnt responses. Therefore, we have examined mouse Tcf7l2 splice variants in neonatal tissues, embryonic stem cells and neural progenitors. By polymerase chain reaction amplification, cloning and sequencing, we identify a large number of alternatively spliced transcripts and report a highly flexible combinatorial repertoire of alternative exons. Many, but not all of the variants exhibit a broad tissue distribution. Moreover, two functionally equivalent versions of the C-clamp, thought to represent an auxiliary DNA-binding domain, were identified. Depending upon promoter context and precise domain composition, TCF4 isoforms exhibit strikingly different transactivation potentials at natural Wnt/β-catenin target promoters. However, differences in C-clamp-mediated DNA binding can only partially explain functional differences among TCF4 variants. Still, the cell-type-specific complement of TCF4 isoforms is likely to be a major determinant for the context-dependent transcriptional output of Wnt/β-catenin signalling.