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

Abstract

BackgroundOverexpression 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.ResultsTranscription 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.ConclusionThe 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.

Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome

“…This latest observation correlates with a recent study showing that DYRK1A is upregulated in trisomic fetal livers and is predicted to be a new potential biomarker for screening DS fetuses. Interestingly, it has been shown that the transcription factor E2F1 increases DYRK1A expression by enhancing promoter activity (52). Added to the recent observation that GATA1s protein failed to repress E2F target genes (53), this might lead to a further increased Dyrk1a expression and potentially explain the cooperation we observed in the Gata1s background and account for the DYRK1A enrichment observed in TMD and DS-AMKL compared with that in non-DS-AMKL and pediatric AML.…”

REST Regulates DYRK1A Transcription in a Negative Feedback Loop

“…The parallel expression of DYRK1A and REST during neurodevelopment further supports the regulatory role of REST in DYRK1A expression. DYRK1A expression can be enhanced by treatment with ␤-amyloid or overexpression of the transcription factor E2F1 (29,38). DYRK1A, located in the Down syndrome critical region on chromosome 21, can phosphorylate microtubule-associated protein Tau at several sites in cultured cells, DYRK1A transgenic mice, and adult DS brains (34 -36).…”

“…The transcription start site of DYRK1A gene was referred as bp ϩ1 according to a previous study (29). Various 5Ј upstream fragments of human DYRK1A gene were amplified by PCR from the 1127-bp fragment and inserted in front of the luciferase reporter gene in pGL3-Basic vector.…”

DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3

“…Underscoring its involvement in cell cycle regulation, the human DYRK1A promoter is itself bound and activated by E2F1 (Maenz et al, 2008), but whether this mechanism directs cell cycle exit by phosphorylating T283 on Cyclin D3 to mark the protein for degradation. Although p38 (Casanovas et al, 2004) and GSK3 (Naderi et al, 2004), have been previously shown to phosphorylate T283 in cell lines, and T283-indpendent degradation of Cyclin D3 has also been reported (Låhne et al, 2006), ours is the first in vivo evidence that DYRK1A plays a major role in murine pre-B and pre-T development.…”