Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control.
Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control.
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DOI：
10.1186/s12915-016-0229-6
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发表时间：
2016-01-22
期刊：
影响因子：
5.4
通讯作者：
Tian B
中科院分区：
文献类型：
--
作者：
Li W;Park JY;Zheng D;Hoque M;Yehia G;Tian B
大多数哺乳动物基因显示选择性裂解和聚腺苷酸化（APA）。先前的研究表明，具有短3 ‘非翻译区（3 ’ utr）的APA亚型在睾丸中优先表达。通过对poly(A) +转录本的3 ‘端区域进行深度测序，我们报道了在小鼠精子发生的第一波中，通过APA广泛缩短3 ’ utr，其中3 ' utr大小是精子中最短的。使用没有APA的基因作为对照，我们发现3'UTR的缩短消除了不稳定因素，如富u元素和转座因子，这些因素在精子发生过程中表现得非常有效。我们还发现，在内含子和外显子中，APA事件的广泛调控可以影响转录本的编码序列和转录起始位点上游反义转录本的全局激活，这表明在精子发生过程中，剪接和转录起始受到调控。重要的是，显示显着3'UTR缩短的基因往往具有对精子进一步成熟至关重要的功能，睾丸特异性基因比普遍表达的基因显示更大的3'UTR缩短，这表明APA与精子发生的功能相关性。有趣的是，与精母细胞相比，具有缩短3 ' utr的基因在精母细胞中往往具有更高的RNA聚合酶II和H3K4me3水平，这些特征先前已知与开放染色质状态相关。我们的数据表明，开放的染色质可能为3 ‘端加工创造了有利的顺式环境，导致精子发生过程中3 ’ utr的整体缩短。由于避开了作用于3'UTR元件的强大mRNA降解机制，缩短3'UTR的mRNA相对稳定。精子中产生的稳定mrna可能对精子成熟后期的蛋白质生产很重要，此时转录在全球范围内停止。本文的在线版本（doi:10.1186/s12915-016-0229-6）包含补充材料，可供授权用户使用。
Most mammalian genes display alternative cleavage and polyadenylation (APA). Previous studies have indicated preferential expression of APA isoforms with short 3’ untranslated regions (3’UTRs) in testes. By deep sequencing of the 3’ end region of poly(A) + transcripts, we report widespread shortening of 3’UTR through APA during the first wave of spermatogenesis in mouse, with 3’UTR size being the shortest in spermatids. Using genes without APA as a control, we show that shortening of 3’UTR eliminates destabilizing elements, such as U-rich elements and transposable elements, which appear highly potent during spermatogenesis. We additionally found widespread regulation of APA events in introns and exons that can affect the coding sequence of transcripts and global activation of antisense transcripts upstream of the transcription start site, suggesting modulation of splicing and initiation of transcription during spermatogenesis. Importantly, genes that display significant 3’UTR shortening tend to have functions critical for further sperm maturation, and testis-specific genes display greater 3’UTR shortening than ubiquitously expressed ones, indicating functional relevance of APA to spermatogenesis. Interestingly, genes with shortened 3’UTRs tend to have higher RNA polymerase II and H3K4me3 levels in spermatids as compared to spermatocytes, features previously known to be associated with open chromatin state. Our data suggest that open chromatin may create a favorable cis environment for 3’ end processing, leading to global shortening of 3’UTR during spermatogenesis. mRNAs with shortened 3’UTRs are relatively stable thanks to evasion of powerful mRNA degradation mechanisms acting on 3’UTR elements. Stable mRNAs generated in spermatids may be important for protein production at later stages of sperm maturation, when transcription is globally halted. The online version of this article (doi:10.1186/s12915-016-0229-6) contains supplementary material, which is available to authorized users.