Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression.
Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression.
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DOI：
10.1101/gad.229328.113
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发表时间：
2013-11-01
影响因子：
10.5
通讯作者：
Mayr C
中科院分区：
文献类型：
--
作者：
Lianoglou S;Garg V;Yang JL;Leslie CS;Mayr C
大多数人类基因使用选择性切割和聚腺苷酸化来产生mRNA转录物，其3 '非翻译区（utr）的长度不同。在这里，Lianoglou等人开发了一种测序方法，3 ' -seq，来测量3 ' UTR异构体在不同人体组织和等基因转化系统中的表达。分析表明，在转化和分化过程中，单UTR基因通常会改变其mRNA丰度水平，而多UTR基因会改变3 ' UTR异构体比例以实现组织特异性。这项研究为如何实现细胞类型特异性基因表达提供了令人惊讶的新见解。超过一半的人类基因使用选择性切割和聚腺苷酸化（ApA）来产生mRNA转录本，这些转录本的3 '非翻译区（utr）的长度不同，从而改变了信息的转录后命运，并可能改变蛋白质的输出。3 ' UTR在组织中的变异程度和ApA的功能作用仍然知之甚少。我们开发了一种称为3 ‘ -seq的测序方法，用于定量绘制各种人体组织和等基因转化系统的转录组的3 ’端。我们发现细胞类型特异性基因表达是通过两个互补程序完成的。组织限制性基因往往具有单个3 ' utr，而大多数普遍转录的基因产生多个3 ' utr。在转化和分化过程中，单UTR基因改变其mRNA丰度水平，而多UTR基因大多改变3 ' UTR异构体比例以实现组织特异性。然而，这两种调控程序针对的是在新细胞类型特征的相同途径和过程中起作用的基因。在转化和分化过程中，我们没有发现3 ' UTR长度的全局变化，而是发现了组织特异性的多UTR基因群体，这些基因改变了它们的3 ' UTR比率；这些3 ' UTR长度的变化在很大程度上独立于mRNA丰度的变化。最后，ApA位点的组织特异性使用似乎是一种通过无处不在表达的microrna改变景观的机制。
A majority of human genes use alternative cleavage and polyadenylation to generate mRNA transcripts that differ in the lengths of their 3′ untranslated regions (UTRs). Here, Lianoglou et al. develop a sequencing method, 3′-seq, to measure 3′ UTR isoform expression across diverse human tissues and isogenic transformation systems. The analyses reveal that during transformation and differentiation, single-UTR genes typically change their mRNA abundance levels, while multi-UTR genes change 3′ UTR isoform ratios to achieve tissue specificity. This study offers surprising new insights into how cell type-specific gene expression is achieved. More than half of human genes use alternative cleavage and polyadenylation (ApA) to generate mRNA transcripts that differ in the lengths of their 3′ untranslated regions (UTRs), thus altering the post-transcriptional fate of the message and likely the protein output. The extent of 3′ UTR variation across tissues and the functional role of ApA remain poorly understood. We developed a sequencing method called 3′-seq to quantitatively map the 3′ ends of the transcriptome of diverse human tissues and isogenic transformation systems. We found that cell type-specific gene expression is accomplished by two complementary programs. Tissue-restricted genes tend to have single 3′ UTRs, whereas a majority of ubiquitously transcribed genes generate multiple 3′ UTRs. During transformation and differentiation, single-UTR genes change their mRNA abundance levels, while multi-UTR genes mostly change 3′ UTR isoform ratios to achieve tissue specificity. However, both regulation programs target genes that function in the same pathways and processes that characterize the new cell type. Instead of finding global shifts in 3′ UTR length during transformation and differentiation, we identify tissue-specific groups of multi-UTR genes that change their 3′ UTR ratios; these changes in 3′ UTR length are largely independent from changes in mRNA abundance. Finally, tissue-specific usage of ApA sites appears to be a mechanism for changing the landscape targetable by ubiquitously expressed microRNAs.
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