Developmental Regulation of Alternative Polyadenylation in an Adult Stem Cell Lineage.
Developmental Regulation of Alternative Polyadenylation in an Adult Stem Cell Lineage.
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成体干细胞谱系中替代多腺苷酸化的发育调节。
DOI：
10.1101/2024.03.18.585561
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Fuller,MargaretT
中科院分区：
文献类型：
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作者：
Gallicchio,Lorenzo;Matias,NeuzaR;Morales-Polanco,Fabian;Nava,Iliana;Stern,Sarah;Zeng,Yi;Fuller,MargaretT
选择性切割和多聚腺苷酸化（阿帕）通常会导致从同一基因座产生具有较长或较短3′ UTR的mRNA同种型，可能影响mRNA的翻译，定位和稳定性。因此，随着细胞分化，发育调节的阿帕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，当精原细胞增殖分化为精母细胞时，有500个基因发生阿帕，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，精母细胞上游多聚腺苷酸化位点的分子机制是理解细胞状态变化的关键。在这里，我们表明，上调PCF11和Cbc的两个组成部分的裂解因子II（CFII），编排阿帕在果蝇精子发生。敲低精母细胞中的PCF11或cbc引起阿帕的失调，许多转录本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。CFII成分在精原细胞中的强制过表达将一些转录物的切割切换到通常在精母细胞中使用的近端位点。我们的研究结果揭示了一种发育机制，其中特异性切割因子表达的变化可以指导细胞类型特异性阿帕在选定的基因。
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.