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Background  Overexpression of the human  DYRK1A  gene due to the presence of a third gene copy in trisomy 21 is thought to play a role in the pathogenesis of Down syndrome. The observation of gene dosage effects in transgenic mouse models implies that subtle changes in expression levels can affect the correct function of the  DYRK1A  gene product. We have therefore characterized the promoter of the human  DYRK1A  gene in order to study its transcriptional regulation.    Results  Transcription start sites of the human  DYRK1A  gene are distributed over 800 bp within a region previously identified as an unmethylated CpG island. We have identified a new alternative noncoding 5'-exon of the  DYRK1A  gene which is located 772 bp upstream of the previously described transcription start site. Transcription of the two splicing variants is controlled by non-overlapping promoter regions that can independently drive reporter gene expression. We found no evidence of cell- or tissue-specific promoter usage, but the two promoter regions differed in their activity and their regulation. The sequence upstream of exon 1A (promoter region A) induced about 10-fold higher reporter gene activity than the sequence upstream of exon 1B (promoter region B). Overexpression of the transcription factor E2F1 increased  DYRK1A  mRNA levels in Saos2 and Phoenix cells and enhanced the activity of promoter region B three- to fourfold.    Conclusion  The identification of two alternatively spliced transcripts whose transcription is initiated from differentially regulated promoters regions indicates that the expression of the  DYRK1A  gene is subject to complex control mechanisms. The regulatory effect of E2F1 suggests that DYRK1A may play a role in cell cycle regulation or apoptosis.

Characterization of the human DYRK1A promoter and its regulation by the transcription factor E2F1