Widespread and extensive lengthening of 3′ UTRs in the mammalian brain

Miura, Pedro; Shenker, Stephen H.; Andreu-Agulló, Celia; Westholm, Jakub Orzechowski; Lai, Eric C.

doi:10.1101/gr.146886.112

Cited by 310 publications

(397 citation statements)

References 42 publications

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“…Other recent findings also support the view that UTRs may play a previously underappreciated role in establishing specific functions of tissues and organs: Throughout the evolution of animals, UTR length has increased along with morphological complexity (40). The brain, arguably the most complex tissue in humans, has much longer UTRs than other tissues (14). The use of emerging technologies that allow precise mapping of transcript start and end sites (41) is expected to provide more insight into this largely unexplored terrain.…”

Section: Differential Exon Usage Provides Versatile Mechanisms To Achmentioning

confidence: 59%

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Drift and conservation of differential exon usage across tissues in primate species

Reyes¹,

Anders²,

Weatheritt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

114

105

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Alternative usage of exons provides genomes with plasticity to produce different transcripts from the same gene, modulating the function, localization, and life cycle of gene products. It affects most human genes. For a limited number of cases, alternative functions and tissue-specific roles are known. However, recent high-throughput sequencing studies have suggested that much alternative isoform usage across tissues is nonconserved, raising the question of the extent of its functional importance. We address this question in a genome-wide manner by analyzing the transcriptomes of five tissues for six primate species, focusing on exons that are 1:1 orthologous in all six species. Our results support a model in which differential usage of exons has two major modes: First, most of the exons show only weak differences, which are dominated by interspecies variability and may reflect neutral drift and noisy splicing. These cases dominate the genome-wide view and explain why conservation appears to be so limited. Second, however, a sizeable minority of exons show strong differences between tissues, which are mostly conserved. We identified a core set of 3,800 exons from 1,643 genes that show conservation of strongly tissue-dependent usage patterns from human at least to macaque. This set is enriched for exons encoding protein-disordered regions and untranslated regions. Our findings support the theory that isoform regulation is an important target of evolution in primates, and our method provides a powerful tool for discovering potentially functional tissue-dependent isoforms.alternative isoform regulation | comparative transcriptomics

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Section: Differential Exon Usage Provides Versatile Mechanisms To Achmentioning

confidence: 59%

“…Tissue-dependent usage (TDU) of exons also affects noncoding parts of transcripts, such as 3′ UTRs, which often contain binding sites for micro-RNAs and RNAbinding proteins (13). For example, the brain tends to have transcripts with much longer UTRs than other tissues (14).…”

mentioning

confidence: 99%

Drift and conservation of differential exon usage across tissues in primate species

Reyes¹,

Anders²,

Weatheritt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

114

105

View full text Add to dashboard Cite

show abstract

“…4). Polyadenylation-site sequencing (PAS-seq) revealed the intergenic regions to represent strongly distal 3′ UTRs 25 (Fig. 2b).…”

Section: Stau1 Binds Paired Alu Elements In 3′ Utrsmentioning

confidence: 99%

Staufen1 senses overall transcript secondary structure to regulate translation

Ricci

Küçükural

Cenik

et al. 2013

Nat Struct Mol Biol

117

180

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Human Staufen1 (Stau1) is a double-stranded RNA (dsRNA)-binding protein implicated in multiple post-transcriptional gene-regulatory processes. Here we combined RNA immunoprecipitation in tandem (RIPiT) with RNase footprinting, formaldehyde cross-linking, sonication-mediated RNA fragmentation and deep sequencing to map Staufen1-binding sites transcriptome wide. We find that Stau1 binds complex secondary structures containing multiple short helices, many of which are formed by inverted Alu elements in annotated 3′ untranslated regions (UTRs) or in 'strongly distal' 3′ UTRs. Stau1 also interacts with actively translating ribosomes and with mRNA coding sequences (CDSs) and 3′ UTRs in proportion to their GC content and propensity to form internal secondary structure. On mRNAs with high CDS GC content, higher Stau1 levels lead to greater ribosome densities, thus suggesting a general role for Stau1 in modulating translation elongation through structured CDS regions. Our results also indicate that Stau1 regulates translation of transcription-regulatory proteins.Staufen proteins are highly conserved dsRNA-binding proteins (dsRBPs) found in most bilateral animals 1 . Mammals contain two Staufen paralogs encoded by different loci. Stau1, Reprints and permissions information is available online at

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“…It can be difficult to predict the functionality of incomplete transcript models. For example, it has been reported that numerous GENCODE lncRNAs may actually represent 39 UTR sequence from protein-coding genes (Miura et al 2013), while a putative CDS could be recharacterized as an NMD candidate if the model is extended at the 39 end. For these reasons, protocols have been devised that capture the true ends of transcripts, i.e., the transcription start site (TSS) and polyadenylation (polyA) site.…”

Section: New Technologies Can Aid Transcript Capture and Completionmentioning

confidence: 99%

Functional transcriptomics in the post-ENCODE era

2013

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The last decade has seen tremendous effort committed to the annotation of the human genome sequence, most notably perhaps in the form of the ENCODE project. One of the major findings of ENCODE, and other genome analysis projects, is that the human transcriptome is far larger and more complex than previously thought. This complexity manifests, for example, as alternative splicing within protein-coding genes, as well as in the discovery of thousands of long noncoding RNAs. It is also possible that significant numbers of human transcripts have not yet been described by annotation projects, while existing transcript models are frequently incomplete. The question as to what proportion of this complexity is truly functional remains open, however, and this ambiguity presents a serious challenge to genome scientists. In this article, we will discuss the current state of human transcriptome annotation, drawing on our experience gained in generating the GENCODE gene annotation set. We highlight the gaps in our knowledge of transcript functionality that remain, and consider the potential computational and experimental strategies that can be used to help close them. We propose that an understanding of the true overlap between transcriptional complexity and functionality will not be gained in the short term. However, significant steps toward obtaining this knowledge can now be taken by using an integrated strategy, combining all of the experimental resources at our disposal.

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Widespread and extensive lengthening of 3′ UTRs in the mammalian brain

Cited by 310 publications

References 42 publications

Drift and conservation of differential exon usage across tissues in primate species

Drift and conservation of differential exon usage across tissues in primate species

Staufen1 senses overall transcript secondary structure to regulate translation

Functional transcriptomics in the post-ENCODE era

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