Regulation of retinoic acid signaling by alternative polyadenylation

选择性聚腺苷酸化（APA）是一种进化保守的转录后基因调控机制。它影响所有基因的70%以上，因此深刻地促进转录组3 '端多样化（TREND）。在大规模的RNAi筛选中，我们最近发现PCF11是近端聚腺苷化的普遍成分，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如何控制发育项目中涉及的中枢信号机制。为此，我们将利用生物信息学、生物化学和功能基因组学方法来解开APA对视黄酸（RA）信号的分子和细胞作用，视黄酸是胚胎发育的一个中心途径，在几种病理生理中起着关键作用。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），以首次了解这种类型的TREND调节对人类疾病的进展、诊断和治疗的影响。

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.