Alternative splicing in multiple sclerosis and other autoimmune diseases

Evsyukova, Irina; Somarelli, Jason A.; Gregory, Simon G.; García-Blanco, Mariano A.

doi:10.4161/rna.7.4.12301

Cited by 72 publications

(68 citation statements)

References 124 publications

(132 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, circularization could regulate gene expression. Alternative splicing has been associated with diverse biologic processes (Faustino and Cooper 2003;Evsyukova et al 2010;Ebert and Bernard 2011;Kalsotra and Cooper 2011), and direct circularization (Model 2) appears to represent a novel form of "alternative" splicing. Because our results show that ecircRNAs are significantly more stable than the associated linear mRNAs (Fig.…”

Section: Discussionmentioning

confidence: 99%

Circular RNAs are abundant, conserved, and associated with ALU repeats

Jeck

Sorrentino

Wang

et al. 2012

RNA

3,660

119

4,516

View full text Add to dashboard Cite

Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known function. To delineate the universe of endogenous circular RNAs, we performed high-throughput sequencing (RNA-seq) of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease, RNase R. We identified >25,000 distinct RNA species in human fibroblasts that contained noncolinear exons (a "backsplice") and were reproducibly enriched by exonuclease degradation of linear RNA. These RNAs were validated as circular RNA (ecircRNA), rather than linear RNA, and were more stable than associated linear mRNAs in vivo. In some cases, the abundance of circular molecules exceeded that of associated linear mRNA by >10-fold. By conservative estimate, we identified ecircRNAs from 14.4% of actively transcribed genes in human fibroblasts. Application of this method to murine testis RNA identified 69 ecircRNAs in precisely orthologous locations to human circular RNAs. Of note, paralogous kinases HIPK2 and HIPK3 produce abundant ecircRNA from their second exon in both humans and mice. Though HIPK3 circular RNAs contain an AUG translation start, it and other ecircRNAs were not bound to ribosomes. Circular RNAs could be degraded by siRNAs and, therefore, may act as competing endogenous RNAs. Bioinformatic analysis revealed shared features of circularized exons, including long bordering introns that contained complementary ALU repeats. These data show that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Circular RNAs are abundant, conserved, and associated with ALU repeats

Jeck

Sorrentino

Wang

et al. 2012

RNA

3,660

119

4,516

View full text Add to dashboard Cite

show abstract

“…These are mediated by the combined action of 59 and 39 splice sites, branch point sequence, and additional regulatory sequences, which, based on their location and mode of action, are classified as either exonic/ intronic splicing enhancers (ESEs or ISEs) or exonic/intronic splicing silencers (ESSs or ISSs) (Garcia-Blanco et al 2004;Lynch 2004;Evsyukova et al 2010). To dissect cis-acting exonic elements that are important for splicing of IL7R exon 6, we created substitution mutants spanning the whole length of exon 6 (sub(1-4) through sub(91-94)), in the context of the splicing reporter minigene pI-12 described previously (Carstens et al 1998;Gregory et al 2007).…”

Section: Resultsmentioning

confidence: 99%

“…Given that exon 6 encodes the transmembrane domain of the receptor (Pleiman et al 1991), its alternative splicing leads to a membrane-bound isoform (rIL7R) when exon 6 is included, and a soluble isoform (sIL7R) when exon 6 is skipped. sIL7R lacks both the transmembrane and cytoplasmic domains of the receptor (Goodwin et al 1990; Korte et al 2000; for review, see Evsyukova et al 2010). Importantly, both isoforms are able to bind IL7 with high affinity (Goodwin et al 1990;Rose et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6

Evsyukova

Bradrick²,

Gregory

et al. 2012

RNA

Self Cite

View full text Add to dashboard Cite

Interleukin 7 receptor, IL7R, is expressed exclusively on cells of the lymphoid lineage, and its expression is crucial for the development and maintenance of T cells. Alternative splicing of IL7R exon 6 results in membrane-bound (exon 6 included) and soluble (exon 6 skipped) IL7R isoforms. Interestingly, the inclusion of exon 6 is affected by a single-nucleotide polymorphism associated with the risk of developing multiple sclerosis. Given the potential association of exon 6 inclusion with multiple sclerosis, we investigated the cis-acting elements and trans-acting factors that regulate exon 6 splicing. We identified multiple exonic and intronic cis-acting elements that impact inclusion of exon 6. Moreover, we utilized RNA affinity chromatography followed by mass spectrometry to identify trans-acting protein factors that bind exon 6 and regulate its splicing. These experiments identified cleavage and polyadenylation specificity factor 1 (CPSF1) among protein-binding candidates. A consensus polyadenylation signal AAUAAA is present in intron 6 of IL7R directly downstream from the 59 splice site. Mutations to this site and CPSF1 knockdown both resulted in an increase in exon 6 inclusion. We found no evidence that this site is used to produce cleaved and polyadenylated mRNAs, suggesting that CPSF1 interaction with intronic IL7R pre-mRNA interferes with spliceosome binding to the exon 6 59 splice site. Our results suggest that competing mRNA splicing and polyadenylation regulate exon 6 inclusion and consequently determine the ratios of soluble to membrane-bound IL7R. This may be relevant for both T cell ontogeny and function and development of multiple sclerosis.

show abstract

“…Alternative splicing is especially prevalent in genes expressed in the nervous and immune systems, in which functional diversity and cellular responsiveness are particularly critical (6). Disruption of normal alternative splicing in such cell types has been linked to an increasing number of human diseases, underscoring the physiologic significance of this mode of gene regulation (7,8). …”

mentioning

confidence: 99%

A Disease-associated Polymorphism Alters Splicing of the Human CD45 Phosphatase Gene by Disrupting Combinatorial Repression by Heterogeneous Nuclear Ribonucleoproteins (hnRNPs)

Motta-Mena

Smith

Mallory

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Alternative splicing is typically controlled by complexes of regulatory proteins that bind to sequences within or flanking variable exons. The identification of regulatory sequence motifs and the characterization of sequence motifs bound by splicing regulatory proteins have been essential to predicting splicing regulation. The activation-responsive sequence (ARS) motif has previously been identified in several exons that undergo changes in splicing upon T cell activation. hnRNP L binds to this ARS motif and regulates ARS-containing exons; however, hnRNP L does not function alone. Interestingly, the proteins that bind together with hnRNP L differ for different exons that contain the ARS core motif. Here we undertake a systematic mutational analysis of the best characterized context of the ARS motif, namely the ESS1 sequence from CD45 exon 4, to understand the determinants of binding specificity among the components of the ESS1 regulatory complex and the relationship between protein binding and function. We demonstrate that different mutations within the ARS motif affect specific aspects of regulatory function and disrupt the binding of distinct proteins. Most notably, we demonstrate that the C77G polymorphism, which correlates with autoimmune disease susceptibility in humans, disrupts exon silencing by preventing the redundant activity of hnRNPs K and E2 to compensate for the weakened function of hnRNP L. Therefore, these studies provide an important example of the functional relevance of combinatorial function in splicing regulation and suggest that additional polymorphisms may similarly disrupt function of the ESS1 silencer.Proper control of protein expression is essential for human health and development. A critical step in determining protein expression is that of pre-mRNA splicing in which non-coding intronic sequences are removed and exonic sequences are joined together through the action of the spliceosome (1). Importantly, the pattern of pre-mRNA splicing for any given gene is not a static choice; rather the inclusion or exclusion of an exon or group of exons can be highly variable (2, 3). Such alternative splicing of an exon is dictated by splicing enhancer or silencer sequences located within the exon or the flanking introns. These regulatory sequences typically bind to trans-acting protein factors that, in turn, interact with components of the spliceosome in such a way that promotes or inhibits the activity of the spliceosome on the exon substrate (2, 3).Alternative splicing alters the protein coding potential of the vast majority of human genes, often in a cell type-specific manner or in response to environmental cues (4, 5). Alternative splicing is especially prevalent in genes expressed in the nervous and immune systems, in which functional diversity and cellular responsiveness are particularly critical (6). Disruption of normal alternative splicing in such cell types has been linked to an increasing number of human diseases, underscoring the physiologic significance of this mode of gene regulation ...

show abstract

Alternative splicing in multiple sclerosis and other autoimmune diseases

Cited by 72 publications

References 124 publications

Circular RNAs are abundant, conserved, and associated with ALU repeats

Circular RNAs are abundant, conserved, and associated with ALU repeats

Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6

A Disease-associated Polymorphism Alters Splicing of the Human CD45 Phosphatase Gene by Disrupting Combinatorial Repression by Heterogeneous Nuclear Ribonucleoproteins (hnRNPs)

Contact Info

Product

Resources

About