Investigation of a regulatory loop between the transcription factor TAL1 and the miR-17-92 Cluster in cell aging and leukemia

转录因子和microRNAs是造血基因表达的关键调控因子。通常在转录因子和microRNAs之间建立调控环，其中给定的转录因子调节特定的microRNA。反过来，这种微小RNA调节转录后转录因子的表达。白血病常与转录因子和microRNAs等调控因子基因表达的突变或表观遗传去调控有关。转录因子TAL1和miR-17-92簇对正常造血很重要，这些调节因子的变化与白血病有关。此外，在不同的细胞系统中，miR-17-92的表达随年龄的变化而变化。我们的数据表明，TAL1和miR-17-92簇的microRNAs可能建立了一个调控环。我们发现TAL1调节miR-17-92的表达，miR-17-92簇的microRNA抑制TAL1的转录后表达。本课题旨在研究TAL1和miR-17-92在正常造血和白血病中的相互调控作用。此外，我们希望研究T细胞和造血干细胞中TAL1和miR-17-92之间调控环的年龄相关变化。这些检查的重点将是TAL1介导的miR-17-92表达的表观遗传学改变。

Transcription factors and microRNAs are key regulators of hematopoietic gene expression. Often regulatory loops between transcription factors and microRNAs are established, in which a given transcription factor regulates a specific microRNA. In turn this microRNA regulates the expression of the transcription factor posttranscriptional. Alterations in gene expression of regulatory factors such as transcription factors and microRNAs by mutation or epigenetic deregulation are often involved in leukemia. The transcription factor TAL1 and the miR-17-92 cluster are important for normal hematopoiesis and alterations in these regulators are associated with leukemia. Furthermore, age related alteration in miR-17-92 expression has been shown in different cell systems. Our data show that TAL1 and the microRNAs of the miR-17-92 cluster might establish a regulatory loop. We found that TAL1 regulates the expression of miR-17-92 and that a microRNA of the miR-17-92 cluster inhibits TAL1 posttranscriptional. In this project we want to study the mutual regulation of TAL1 and miR-17-92 in normal hematopoiesis and in leukemia. Furthermore, we want to study age related alterations in the regulatory loop between TAL1 and miR-17-92 in T cells and hematopoietic stem cells. A focus of these examinations will be TAL1 mediated epigenetic alterations of miR-17-92 expression.