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.

中文翻译：

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人类 DYRK1A 启动子的表征及其转录因子 E2F1 的调控。

背景 由于 21 三体中第三个基因拷贝的存在，人 DYRK1A 基因的过度表达被认为在唐氏综合征的发病机制中起作用。在转基因小鼠模型中观察基因剂量效应意味着表达水平的细微变化会影响 DYRK1A 基因产物的正确功能。因此，我们对人类 DYRK1A 基因的启动子进行了表征，以研究其转录调控。结果 人类 DYRK1A 基因的转录起始位点分布在先前被确定为未甲基化 CpG 岛的区域内超过 800 bp。我们已经确定了 DYRK1A 基因的一个新的替代非编码 5'-外显子，它位于先前描述的转录起始位点上游 772 bp。两个剪接变体的转录由非重叠的启动子区域控制，可以独立驱动报告基因表达。我们没有发现细胞或组织特异性启动子使用的证据，但两个启动子区域的活性和调控不同。外显子 1A 上游序列（启动子区域 A）诱导的报告基因活性比外显子 1B 上游序列（启动子区域 B）高约 10 倍。转录因子 E2F1 的过表达增加了 Saos2 和 Phoenix 细胞中的 DYRK1A mRNA 水平，并将启动子区域 B 的活性提高了三到四倍。结论 鉴定出两个可变剪接转录本，其转录是从差异调节的启动子区域启动的，表明 DYRK1A 基因的表达受复杂的控制机制影响。E2F1 的调节作用表明 DYRK1A 可能在细胞周期调节或细胞凋亡中发挥作用。