U1-like snRNAs lacking complementarity to canonical 5′ splice sites

Kyriakopoulou, Christina; Larsson, Pontus; Liu, Lei; Schuster, Jens; Söderbom, Fredrik; Kirsebom, Leif A.; Virtanen, Anders

doi:10.1261/rna.26506

Cited by 30 publications

(42 citation statements)

References 54 publications

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“…We have focused our attention on the entire U1 snRNA class I pseudogene locus and shown that 50% of the vU1 snRNA genes annotated within this 6.8-Mb region express an snRNA in HeLa cells and that all 21 vU1 snRNA genes are active, at varying levels, in hESCs. In addition, three other vU1 snRNAs (U1A5, U1A6, and U1A7) were also previously isolated from HeLa cells (Kyriakopoulou et al 2006). A ''BLAT'' search of their sequences indicates that they map to different locations on the human genome.…”

Section: Discussionmentioning

confidence: 99%

“…Since the U1 snRNA is not translated into a protein, active pseudogenes could generate variant functional snRNAs. It has been known for some time that minor U1-like snRNAs, with variation to the human U1 snRNA exist, but to date, their function remains elusive (Patton and Wieben 1987;Lund 1988;Kyriakopoulou et al 2006). We questioned whether variant U1 snRNAs, encoded by class I pseudogenes, could play a role in regulating gene expression in vivo.…”

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confidence: 96%

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Differentially expressed, variant U1 snRNAs regulate gene expression in human cells

et al. 2012

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Human U1 small nuclear (sn)RNA, required for splicing of pre-mRNA, is encoded by genes on chromosome 1 (1p36). Imperfect copies of these U1 snRNA genes, also located on chromosome 1 (1q12-21), were thought to be pseudogenes. However, many of these “variant” (v)U1 snRNA genes produce fully processed transcripts. Using antisense oligonucleotides to block the activity of a specific vU1 snRNA in HeLa cells, we have identified global transcriptome changes following interrogation of the Affymetrix Human Exon ST 1.0 array. Our results indicate that this vU1 snRNA regulates expression of a subset of target genes at the level of pre-mRNA processing. This is the first indication that variant U1 snRNAs have a biological function in vivo. Furthermore, some vU1 snRNAs are packaged into unique ribonucleoproteins (RNPs), and many vU1 snRNA genes are differentially expressed in human embryonic stem cells (hESCs) and HeLa cells, suggesting developmental control of RNA processing through expression of different sets of vU1 snRNPs.

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Section: Discussionmentioning

confidence: 99%

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confidence: 96%

Differentially expressed, variant U1 snRNAs regulate gene expression in human cells

et al. 2012

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“…Finally, we used U1-specific RNA decoys (Roca and Krainer 2009) to confirm that all of the tested 59ss in the SMN1/2 contexts are indeed recognized by U1 and not by other U1-like snRNAs (Kyriakopoulou et al 2006). These vector-driven RNA decoys sequester endogenous U1, resulting in the loss of 59ss recognition and, consequently, in SMN1/2 exon 7 skipping.…”

Section: Registers With Bulges At the 59 End Of U1mentioning

confidence: 97%

Widespread recognition of 5′ splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides

Roca¹,

Akerman²,

Gaus³

et al. 2012

Genes Dev.

137

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An established paradigm in pre-mRNA splicing is the recognition of the 59 splice site (59ss) by canonical basepairing to the 59 end of U1 small nuclear RNA (snRNA). We recently reported that a small subset of 59ss base-pair to U1 in an alternate register that is shifted by 1 nucleotide. Using genetic suppression experiments in human cells, we now demonstrate that many other 59ss are recognized via noncanonical base-pairing registers involving bulged nucleotides on either the 59ss or U1 RNA strand, which we term ''bulge registers.'' By combining experimental evidence with transcriptome-wide free-energy calculations of 59ss/U1 base-pairing, we estimate that 10,248 59ss (~5% of human 59ss) in 6577 genes use bulge registers. Several of these 59ss occur in genes with mutations causing genetic diseases and are often associated with alternative splicing. These results call for a redefinition of an essential element for gene expression that incorporates these registers, with important implications for the molecular classification of splicing mutations and for alternative splicing.[Keywords: 59 splice site; U1 small nuclear RNA; base-pairing register; bulged nucleotide; splicing mutation; alternative splicing] Supplemental material is available for this article. Pre-mRNA splicing is an essential processing step for the expression of ;90% of protein-coding human genes and relies on conserved sequence elements at both ends of introns, termed splice sites (Sheth et al. 2006;Wahl et al. 2009). These elements are highly diverse, considering that thousands of different sequences act as naturally occurring splice sites in the human transcriptome (Sahashi et al. 2007;Roca and Krainer 2009). The characterization of these sequence elements and the factors that recognize them has been essential for predicting exons in new genes, for the study of alternative splicing (Nilsen and Graveley 2010), and for classifying mutations in these elements that cause human genetic diseases (Buratti et al. 2007).Typically, the strength of a splice site (or splice site score) is estimated by algorithms that measure its concordance to matrices built using large collections of splice sites (Senapathy et al. 1990;Brunak et al. 1991;Yeo and Burge 2004;Sahashi et al. 2007;Hartmann et al. 2008). These methods implicitly assume that all of the sequences used to build the matrix are recognized by the same mechanism. However, there are cases in which the splice site score does not reflect the strength of the splice site determined experimentally (Roca and Krainer 2009), highlighting the limitations of these tools. Furthermore, the recognition mechanisms for many splice sites predicted to be weak are poorly understood.Splicing of >99% of pre-mRNA introns is catalyzed by the major spliceosome, a dynamic macromolecular machine composed of five small nuclear RNAs (snRNAs) and associated polypeptides, plus many other protein factors (Wahl et al. 2009). The U1 small nuclear ribonucleoprotein particle (snRNP), comprising the U1 snRNA and 10 polypeptides (Pomeranz K...

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“…Distinguishable snRNA paralogs that are often differentially expressed have previously been reported for a diverse collection of major spliceosmal snRNAs including U1 snRNAs in insects [43,64,77], Xenopus [12], and human [39], U2 snRNAs in Dictyostelium [29], sea urchin [80] and silk moth [77], U5 snRNAs in human [79], sea urchin [52], and Drosophilids [8], U6 snRNAs in silk moth [78] and human [85,14].…”

Section: Phylogenetic Analysis and Paralogsmentioning

confidence: 99%

“…Very recently, however, some of these variants have been studied in more details, see e.g. [64,8,39,77,29,78] and the references therein. The only systematic study that we are aware of is the recent comprehensive analysis of 11 insect genomes [53] which reported that phylogenetic gene trees of insect snRNAs do not provide clear support for discernible paralog groups of U1 and/or U5 snRNAs that would correspond to the variants with tissue-specific expression patterns.…”

Section: Introductionmentioning

confidence: 99%

Evolution of Spliceosomal snRNA Genes in Metazoan Animals

2008

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While studies of the evolutionary histories of protein families are common place, little is known on noncoding RNAs beyond microRNAs and some snoRNAs. Here we investigate in detail the evolutionary history of the 9 spliceosomal snRNA families (U1, U2, U4, U5, U6, U11, U12, U4atac, and U6atac) across the completely or partially sequenced genomes of metazoan animals. Representatives of the five major spliceosomal snRNAs were found in all genomes. None of the minor splicesomal snRNAs was detected in Nematodes and in the shotgun traces of Oikopleura dioica, while in all other animal genomes at most one of them is missing. Although snRNAs are present in multiple copies in most genomes, distinguishable paralog groups are not stable over long evolutionary times, although they appear independently in several clades. In general, animal snRNA secondary structures are highly conserved, albeit in particular U11 and U12 in insects exhibit dramatic variations. An analysis of genomic context of snRNAs reveals that they behave like mobile elements, exhibiting very little syntenic conservation.

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U1-like snRNAs lacking complementarity to canonical 5′ splice sites

Cited by 30 publications

References 54 publications

Differentially expressed, variant U1 snRNAs regulate gene expression in human cells

Differentially expressed, variant U1 snRNAs regulate gene expression in human cells

Widespread recognition of 5′ splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides

Evolution of Spliceosomal snRNA Genes in Metazoan Animals

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