U1 snRNP Telescripting Roles in Transcription and Its Mechanism.
U1 snRNP Telescripting Roles in Transcription and Its Mechanism.
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DOI：
10.1101/sqb.2019.84.040451
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Dreyfuss, Gideon
中科院分区：
文献类型：
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作者：
Di, Chao;So, Byung Ran;Dreyfuss, Gideon
套刻是一种基本的共转录基因调控过程，其依赖于U1 snRNP（U1）来抑制RNA聚合酶II（Pol II）转录物中的过早3 '末端切割和多聚腺苷酸化（PCPA），这是数千种蛋白质编码（pre-mRNAs）和长非编码（lncRNA）基因的全长转录所必需的。就像U1在剪接中的作用一样，剪接需要U1 snRNA与新生转录物的碱基配对。用U1 snRNA反义吗啉代寡核苷酸（U1 AMO）抑制U1碱基配对模拟来自人类组织中隐蔽聚腺苷酸化信号（PAS）的广泛PCPA，包括内含子和最后外显子“3 '非翻译区（3' UTR）中的PCPA。U1转录-PCPA平衡变化产生不同的RNA，这取决于它在基因中发生的位置。与短基因相比，长基因是高度U1-转录依赖的，因为在内含子中有PAS。与管家基因和短基因中的急性细胞应激反应基因相比，长基因中细胞周期控制、分化和发育功能的富集揭示了哺乳动物基因组中的基因大小-功能关系。在后生动物进化中，这种极化通过先前无法解释的内含子扩展而增加，这表明U1转录可以改变全球基因表达的优先顺序。我们表明，调节U1的可用性可以深刻地改变细胞表型，如癌细胞的迁移和侵袭，强调了U1稳态的关键作用，并建议它作为一个潜在的治疗目标。我们描述了一个复合物的U1与切割和多聚腺苷酸化因子，沉默PAS的内含子和3'非翻译区，这给洞察U1的转录机制和转录延伸调控。
Telescripting is a fundamental cotranscriptional gene regulation process that relies on U1 snRNP (U1) to suppress premature 3'-end cleavage and polyadenylation (PCPA) in RNA polymerase II (Pol II) transcripts, which is necessary for full-length transcription of thousands of protein-coding (pre-mRNAs) and long noncoding (lncRNA) genes. Like U1 role in splicing, telescripting requires U1 snRNA base-pairing with nascent transcripts. Inhibition of U1 base-pairing with U1 snRNA antisense morpholino oligonucleotide (U1 AMO) mimics widespread PCPA from cryptic polyadenylation signals (PASs) in human tissues, including PCPA in introns and last exons' 3'-untranslated regions (3' UTRs). U1 telescripting-PCPA balance changes generate diverse RNAs depending on where in a gene it occurs. Long genes are highly U1-telescripting-dependent because of PASs in introns compared to short genes. Enrichment of cell cycle control, differentiation, and developmental functions in long genes, compared to housekeeping and acute cell stress response genes in short genes, reveals a gene size-function relationship in mammalian genomes. This polarization increased in metazoan evolution by previously unexplained intron expansion, suggesting that U1 telescripting could shift global gene expression priorities. We show that that modulating U1 availability can profoundly alter cell phenotype, such as cancer cell migration and invasion, underscoring the critical role of U1 homeostasis and suggesting it as a potential target for therapies. We describe a complex of U1 with cleavage and polyadenylation factors that silences PASs in introns and 3' UTR, which gives insights into U1 telescripting mechanism and transcription elongation regulation.