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Understanding the Noise: Spliceosomal snRNA Profiling
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The concept of the gene has been constantly challenged by new discoveries in the life sciences. Recent challenging observations include the high frequency of alternative splicing events and the common transcription of non-protein-coding-RNAs (ncRNAs) from the genome. The latter has long been considered noise in biological systems. Multiple lines of evidence from genomic studies indicate that alternative splicing and ncRNA play important roles in expanding proteome diversity in eukaryotes. Here, the aim is to find the link between alternative splicing and ncRNAs by studying the expression profile of the spliceosomal snRNAs (U snRNA).

Spliceosomal snRNAs are essential for pre-mRNA splicing in eukaryotes. They participate in splice site selection, recruitment of protein factors and catalyzing the splicing reaction. Because of this, both the abundance and diversity of U snRNAs were expected to be large. In our study we deeply analyzed the U snRNA population in primates using a combination of bioinformatical, biochemical and high throughput sequencing approaches. This transcriptome profiling has revealed that human, chimpanzee and rhesus have similar U snRNA populations, i.e. the vast majority of U snRNAs originate from few well-defined gene loci and the heterogeneity observed in U snRNA populations was largely due to the presence of SNPs at these loci. It seems that the gene loci that could potentially encode a significantly heterogeneous population of U snRNAs are mostly silent. Only few minority transcripts were detected in our study, and among them three U1-like snRNAs might play a role in the regulation of alternative splicing by recognizing non-canonical splicing sites.

Mutations of U snRNA have been shown to impact the splicing process. Therefore, our study provides a reference to study the biological significance of SNPs in U snRNA genes and their association with diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 45 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 924
Keyword [en]
ncRNA, snRNA, U1, splice site, alternative splicing, high-throughput sequencing, 454, SNP
National Category
Natural Sciences Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
URN: urn:nbn:se:uu:diva-172403ISBN: 978-91-554-8341-8 (print)OAI: oai:DiVA.org:uu-172403DiVA: diva2:514637
Public defence
2012-05-24, B41, Husargatan 3, Biomedicinskt Centrum, Uppsala University, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2012-05-02 Created: 2012-04-10 Last updated: 2012-08-01Bibliographically approved
List of papers
1. U1-like snRNAs lacking complementarity to canonical 5' splice sites
Open this publication in new window or tab >>U1-like snRNAs lacking complementarity to canonical 5' splice sites
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2006 (English)In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 12, no 9, 1603-1611 p.Article in journal (Refereed) Published
Abstract [en]

We have detected a surprising heterogeneity among human spliceosomal U1 small nuclear RNA (snRNA). Most interestingly, we have identified three U1 snRNA variants that lack complementarity to the canonical 5' splice site (5'SS) GU dinucleotide. Furthermore, we have observed heterogeneity among the identified variant U1 snRNA genes caused by single nucleotide polymorphism (SNP). The identified snRNAs were ubiquitously expressed in a variety of human tissues representing different stages of development and displayed features of functional spliceosomal snRNAs, i.e., trimethylated cap structures, association with Sm proteins and presence in nuclear RNA-protein complexes. The unanticipated heterogeneity among spliceosomal snRNAs could contribute to the complexity of vertebrates by expanding the coding capacity of their genomes.

Keyword
U1 snRNP, mRNA splicing, noncanonical 5 ' splice site, SNP, genome complexity
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-97962 (URN)10.1261/rna.26506 (DOI)000240145400001 ()16829670 (PubMedID)
Available from: 2009-01-01 Created: 2009-01-01 Last updated: 2016-09-09Bibliographically approved
2. Construction and deep sequencing of cDNA libraries representing medium-sized RNA
Open this publication in new window or tab >>Construction and deep sequencing of cDNA libraries representing medium-sized RNA
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Transcriptome analysis has recently become feasible with the application of RNA-seq, the high-throughput sequencing analysis of RNAs through cDNA synthesis. Current transcriptome analysis approaches are limited to analysis of long (>200 nts) or short (~20 nts) RNAs. Here we describe an approach that can be used for the analysis of the medium-sized (~200 nts) RNA transcriptome, which reveals the full-length sequence of RNAs at the single molecule level. Our approach can easily be adapted to generate libraries that are suitable for sequencing by several of the currently used next-generation platforms.

Keyword
high-throughput sequencing, 454, snRNA, cDNA library
National Category
Natural Sciences Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-172422 (URN)
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2012-08-01
3. The primate spliceosomal snRNA transcriptome as revealed by deep sequencing
Open this publication in new window or tab >>The primate spliceosomal snRNA transcriptome as revealed by deep sequencing
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Small nuclear RNAs (snRNAs) in combination with protein factors form the spliceosomes and are essential for pre-mRNA splicing. In this study we have characterized the spliceosomal snRNA (U snRNA) transcriptome in human, chimpanzee and rhesus using a recently developed high-throughput sequencing approach. Our study has revealed that the U snRNA transcriptomes of all three primates have a similar composition and that the vast majority of the U snRNAs originate from a few well-defined loci. We have detected some heterogeneity in the U snRNA transcriptomes that is primarily caused by the presence of SNPs in the few expressed loci that we have identified.

National Category
Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-172428 (URN)
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2012-08-01

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Conze, Lei Liu

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