Regulation of retinoic acid signaling by alternative polyadenylation

选择性多聚腺苷化(APA)是一种进化保守的转录后基因调控机制。它影响了超过70%的基因，从而深刻地促进了转录组3‘端的多样化(趋势)。在大规模的RNAi筛选中，我们最近发现PCF11是近端多聚腺苷的普遍成分，在分化和去分化中起关键作用。然而，潜在的机制在很大程度上仍然不清楚。我们现在打算探索APA如何控制参与发育计划的中央信号机制。为此，我们将利用生物信息学、生化和功能基因组学方法来解开APA对维甲酸(RA)信号通路的分子和细胞效应。维甲酸信号通路是胚胎发育的中心途径，在几种病理生理中具有关键作用。最终，这些发现将被转化为RA依赖的疾病模型(急性早幼粒细胞白血病)，以获得关于这种类型的趋势调节对人类疾病的进展、诊断和治疗的影响的初步见解。

Alternative polyadenylation (APA) is an evolutionarily conserved mechanism of posttranscriptional gene regulation. It affects more than 70% of all genes and thereby profoundly contributes to transcriptome 3’end diversification (TREND). In a large-scale RNAi screening, we recently discovered PCF11 as a pervasive component for proximal polyadenylation with a critical role in differentiation and dedifferentiation. However, the underlying mechanisms remained largely obscure. We now intend to explore how APA controls central signaling mechanisms involved in developmental programs. To this end, we will make use of bioinformatical, biochemical, and functional genomic approaches to disentangle the molecular and cellular effects of APA on retinoic acid (RA) signaling, a central pathway in embryonic development with a critical function in several pathophysiologies. Ultimately, these findings will be translated into an RA-dependent disease model (acute promyelocytic leukemia) to obtain first insights on the impact of this type of TREND regulation on progression, diagnosis and therapy of a human disease.