The mouse RNase 4 and RNase 5/ang 1 locus utilizes dual promoters for tissue-specific expression

The ribonuclease A (RNase A) superfamily has been the subject of extensive studies in the areas of protein evolution, structure and biochemistry and are exciting molecules in that they appear to be responding to unique selection pressures, generating proteins capable of multiple and diverse activities. The RNase 4 and RNase 5/ang 1 shared locus breaks a pattern that is otherwise canonical among the members of the RNase A gene superfamily. Conserved among humans, mice and rats, the locus includes two non-coding exons followed by two distinct exons encoding RNase 4 and RNase 5/ang 1. Transcription from this locus is controlled by differential splicing and tissue-specific expression from promoters located 5' to each of the non-coding exons. Promoter 1, 5' to exon I, is universally active, while Promoter 2, 5' to exon II, is active only in hepatic cells in promoter assays in vitro. Transcription from Promoter 2 is dependent on an intact HNF-1 consensus binding site which binds the transcription factor HNF-1alpha. In summary, RNase 4 and RNase 5/ang 1 are unique among the RNase A ribonuclease genes in that they maintain a complex gene locus that is conserved across species with transcription initiated from tissue-specific dual promoters followed by differential exon splicing.