Alternative cleavage and polyadenylation (APA) often results in production of mRNA isoforms with either longer or shorter 3′ UTRs from the same genetic locus, potentially impacting mRNA translation, localization, and stability. Developmentally regulated APA can thus make major contributions to cell type-specific gene expression programs as cells differentiate. During Drosophila spermatogenesis, ∼500 genes undergo APA when proliferating spermatogonia differentiate into spermatocytes, producing transcripts with shortened 3′ UTRs, leading to profound stage-specific changes in the proteins expressed. The molecular mechanisms that specify usage of upstream polyadenylation sites in spermatocytes are thus key to understanding the changes in cell state. Here, we show that upregulation of PCF11 and Cbc, the two components of cleavage factor II (CFII), orchestrates APA during Drosophila spermatogenesis. Knockdown of PCF11 or cbc in spermatocytes caused dysregulation of APA, with many transcripts normally cleaved at a proximal site in spermatocytes now cleaved at their distal site, as in spermatogonia. Forced overexpression of CFII components in spermatogonia switched cleavage of some transcripts to the proximal site normally used in spermatocytes. Our findings reveal a developmental mechanism where changes in expression of specific cleavage factors can direct cell type-specific APA at selected genes.

中文翻译：

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调节成体干细胞谱系中选择性多腺苷酸化的发育机制


选择性切割和多聚腺苷酸化 (APA) 通常会导致产生来自同一基因位点的具有较长或较短 3' UTR 的 mRNA 亚型，可能会影响 mRNA 翻译、定位和稳定性。因此，随着细胞分化，发育调节的 APA 可以对细胞类型特异性基因表达程序做出重大贡献。在果蝇精子发生过程中，当增殖的精原细胞分化为精母细胞时，约 500 个基因经历 APA，产生 3'UTR 缩短的转录本，导致表达的蛋白质发生深刻的阶段特异性变化。因此，指定精母细胞中上游聚腺苷酸化位点的使用的分子机制是理解细胞状态变化的关键。在这里，我们表明，裂解因子 II (CFII) 的两个成分 PCF11 和 Cbc 的上调在果蝇精子发生过程中协调 APA。精母细胞中PCF11或cbc的敲低导致 APA 失调，许多转录物通常在精母细胞的近端位点裂解，现在在其远端位点裂解，如在精原细胞中。精原细胞中 CFII 成分的强制过度表达将一些转录物的裂解转移到精母细胞中通常使用的近端位点。我们的研究结果揭示了一种发育机制，其中特定裂解因子表达的变化可以指导细胞类型特异性 APA 针对选定的基因。