Developmentally regulated alternate 3' end cleavage of nascent transcripts controls dynamic changes in protein expression in an adult stem cell lineage.
Developmentally regulated alternate 3' end cleavage of nascent transcripts controls dynamic changes in protein expression in an adult stem cell lineage.
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DOI：
10.1101/gad.349689.122
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发表时间：
2022-08-01
影响因子：
10.5
通讯作者：
Fuller, Margaret T
中科院分区：
文献类型：
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作者：
Berry, Cameron W;Olivares, Gonzalo H;Gallicchio, Lorenzo;Ramaswami, Gokul;Glavic, Alvaro;Olguin, Patricio;Li, Jin Billy;Fuller, Margaret T
在这项研究中，Berry等人。鉴定了>；500果蝇基因，在增殖的精原细胞中有长3‘非编码区，但在精母细胞分化过程中由于APA而有短的3’非编码区。总体而言，他们表明，发育受调控的另一个位点的选择，在那里进行终止新生转录本的3‘端切割，可以深刻地影响细胞在分化谱系中通过连续步骤前进时表达的一组蛋白质。选择性多聚腺苷酸化(APA)产生不同位置的3‘裂解位点的转录异构体，导致产生不同长度的3’UTRs的mRNA异构体。虽然广泛存在，但APA在细胞、组织和生物体生物学中的作用一直存在争议。我们鉴定了>；500果蝇基因，在增殖的精原细胞中表达长3‘非编码区，但在精母细胞分化过程中由于APA而表达短的3’非编码区。我们表明，3‘端切割位点的阶段特异性选择可以通过在远端切割位点附近排列一个典型的多聚腺苷酸化信号(PAS)来调节，而在近端切割位点附近则有一个变异的或没有可识别的PAS信号。分化细胞中3‘UTRs较短的转录本的出现与精原细胞中编码蛋白表达的变化有关，精原细胞中编码蛋白的表达从OFF变为ON，反之亦然。多聚体梯度分离显示>；250个基因中长3‘非编码区和短3’非编码区的mRNA异构体发生了不同的迁移，这与翻译状态在不同阶段的戏剧性变化相一致。因此，发育调节的另一个位点的选择，在那里进行终止新生转录本的3‘端切割，可以深刻地影响随着细胞在分化谱系中的连续步骤而前进时表达的一组蛋白质。
In this study, Berry et al. identified >500 Drosophila genes that express mRNA isoforms with a long 3′ UTR in proliferating spermatogonia but a short 3′ UTR in differentiating spermatocytes due to APA. Overall, they show that the developmentally regulated choice of an alternative site at which to make the 3′ end cut that terminates nascent transcripts can profoundly affect the suite of proteins expressed as cells advance through sequential steps in a differentiation lineage. Alternative polyadenylation (APA) generates transcript isoforms that differ in the position of the 3′ cleavage site, resulting in the production of mRNA isoforms with different length 3′ UTRs. Although widespread, the role of APA in the biology of cells, tissues, and organisms has been controversial. We identified >500 Drosophila genes that express mRNA isoforms with a long 3′ UTR in proliferating spermatogonia but a short 3′ UTR in differentiating spermatocytes due to APA. We show that the stage-specific choice of the 3′ end cleavage site can be regulated by the arrangement of a canonical polyadenylation signal (PAS) near the distal cleavage site but a variant or no recognizable PAS near the proximal cleavage site. The emergence of transcripts with shorter 3′ UTRs in differentiating cells correlated with changes in expression of the encoded proteins, either from off in spermatogonia to on in spermatocytes or vice versa. Polysome gradient fractionation revealed >250 genes where the long 3′ UTR versus short 3′ UTR mRNA isoforms migrated differently, consistent with dramatic stage-specific changes in translation state. Thus, the developmentally regulated choice of an alternative site at which to make the 3′ end cut that terminates nascent transcripts can profoundly affect the suite of proteins expressed as cells advance through sequential steps in a differentiation lineage.