Institute for Transfusion Medicine and Immunohematology, and German Red Cross Blood Service BaWüHe, Goethe University, Sandhofstraße 1, 60528, Frankfurt, Germany.
Institute for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
Sci Rep. 2020 Dec 8;10(1):21438. doi: 10.1038/s41598-020-78629-z.
A network of gene regulatory factors such as transcription factors and microRNAs establish and maintain gene expression patterns during hematopoiesis. In this network, transcription factors regulate each other and are involved in regulatory loops with microRNAs. The microRNA cluster miR-17-92 is located within the MIR17HG gene and encodes six mature microRNAs. It is important for hematopoietic differentiation and plays a central role in malignant disease. However, the transcription factors downstream of miR-17-92 are largely elusive and the transcriptional regulation of miR-17-92 is not fully understood. Here we show that miR-17-92 forms a regulatory loop with the transcription factor TAL1. The miR-17-92 cluster inhibits expression of TAL1 and indirectly leads to decreased stability of the TAL1 transcriptional complex. We found that TAL1 and its heterodimerization partner E47 regulate miR-17-92 transcriptionally. Furthermore, miR-17-92 negatively influences erythroid differentiation, a process that depends on gene activation by the TAL1 complex. Our data give example of how transcription factor activity is fine-tuned during normal hematopoiesis. We postulate that disturbance of the regulatory loop between TAL1 and the miR-17-92 cluster could be an important step in cancer development and progression.
一个基因调控因子网络，如转录因子和 microRNAs，在造血过程中建立和维持基因表达模式。在这个网络中，转录因子相互调节，并与 microRNAs 形成调节环。miR-17-92 微RNA 簇位于 MIR17HG 基因内，编码六个成熟的 microRNAs。它对造血分化很重要，并在恶性疾病中发挥核心作用。然而，miR-17-92 的下游转录因子在很大程度上尚不清楚，miR-17-92 的转录调控也不完全清楚。在这里，我们表明 miR-17-92 与转录因子 TAL1 形成一个调节环。miR-17-92 簇抑制 TAL1 的表达，并间接导致 TAL1 转录复合物的稳定性降低。我们发现 TAL1 及其异二聚体伙伴 E47 转录调控 miR-17-92。此外，miR-17-92 负调控红细胞分化，这个过程依赖于 TAL1 复合物对基因的激活。我们的数据为转录因子活性在正常造血过程中如何被精细调节提供了范例。我们推测，TAL1 和 miR-17-92 簇之间的调节环的紊乱可能是癌症发展和进展的重要步骤。
