The Relevance of HNF4alpha Splice Variants in Differential Transcriptional Regulation

Further complexity of gene control by HNF-4alpha transcription factors can be anticipated by the differential splicing of the 10 initially identified exons of the HNF-4alpha gene (Nakhei et al., 1998). Thus, so far, seven distinct splice variants have been identified in human and murine cDNA samples. HNF-4alpha1 represents the initially identified transcript, and HNF-4alpha2 through HNF-4alpha7 are the splice variants identified subsequently (Sladek et al., 1990; Hata et al., 1992, 1995; Chartier et al., 1994; Drewes et al., 1996; Kritis et al., 1996; Furuta et al., 1997; Nakhei et al., 1998). In all HNF-4alpha splice variants the DNA-binding domain remains unchanged (Viollet et al., 1997; Nakhei et al., 1998). The impact of these different splice variants on the regulation of downstream target gene regulation remains largely to be determined. The consequences of the existence of different splice variants on the regulation of gene transcription are still not fully understood. Within the 5'-untranslated region of HNF-4alpha, the two splice variants HNF4alpha2 and HNF4alpha3 with additional exons were detected. Both HNF-4alpha splice variants share HNF-4 binding sites with HNF-4alpha1 but have lower DNA binding activities and weaker trans-activation potential than HNF-4alpha1 (Holewa et al., 1997). In cotransfection experiments, evidence was obtained that HNF-4alpha1 is significantly less active than HNF-4alpha2 and that the HNF-4alpha splice variant HNF-4alpha4 has no detectable trans-activation potential. Therefore, the differential expression of distinct HNF-4alpha proteins may play a key role in the differential transcriptional regulation of HNF-4-dependent genes (Drewes etal., 1996).

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