Alternative polyadenylation (APA) plays a critical role in regulating gene expression. However, the balance between genome-encoded APA processing and autoregulation by APA modulating RNA binding protein (RBP) factors is not well understood. We discovered two potent small-molecule modulators of APA (T4 and T5) that promote distal-to-proximal (DtoP) APA usage in multiple transcripts. Monotonically responsive APA events, induced by short exposure to T4 or T5, were defined in the transcriptome, allowing clear isolation of the genomic sequence features and RBP motifs associated with DtoP regulation. We found that longer vulnerable introns, enriched with distinctive A-rich motifs, were preferentially affected by DtoP APA, thus defining a core set of genes with genomically encoded DtoP regulation. Through APA response pattern and compound-small interfering RNA epistasis analysis of APA-associated RBP factors, we further demonstrated that DtoP APA usage is partly modulated by altered autoregulation of polyadenylate binding nuclear protein-1 signaling.

中文翻译：

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基因组编码的聚腺苷酸化的转录组动力学的解码和小聚腺苷酸化的小分子调节剂的自动调节。

替代性聚腺苷酸化（APA）在调节基因表达中起关键作用。但是，人们对基因组编码的APA加工与通过APA调节RNA结合蛋白（RBP）因子进行自动调节之间的平衡了解甚少。我们发现了两个有效的APA小分子调节剂（T4和T5），可在多个转录物中促进从远端到近端（DtoP）APA的使用。在转录组中定义了由短时暴露于T4或T5诱导的单调响应APA事件，从而可以清楚地分离与DtoP调控相关的基因组序列特征和RBP基序。我们发现，较长的易损内含子，富含独特的富含A的基序，优先受到DtoP APA的影响，从而定义了具有基因组编码的DtoP调控的一组核心基因。