Minor introns are embedded molecular switches regulated by highly unstable U6atac snRNA

Younis, Ihab; Dittmar, Kimberly; Wang, Wei; Foley, Shawn W.; Berg, Michael G.; Hu, Karen Y; Wei, Zhi; Wan, Lili; Dreyfuss, Gideon

doi:10.7554/elife.00780

Cited by 81 publications

(112 citation statements)

References 47 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…However, recent findings suggest that regulation of U12-type splicing may be more complicated than previously thought. For example, p38MAPK-mediated up-regulation of the otherwise rate-limiting levels of U6atac in HeLa cells appears to constitute a sophisticated regulatory mechanism to facilitate the rapid mobilization of critical U12-type intron-containing transcripts in response to growth stimuli (14). Because many of these transcripts encode genes with functions in mRNA production, such an amplification of U12-type splicing activity is likely to generate a robust transcriptome-wide response.…”

Section: Rnpc3 Deficiency Leads To a Pleiotropic Phenotype In Developingmentioning

confidence: 99%

“…Since its discovery two decades ago, the existence of this highly conserved, second splicing pathway has been an intriguing aspect of gene expression. Interestingly, U12-type introns are nonrandomly distributed across the genome (11) and their removal is thought to be rate-limiting in the generation of mature mRNAs (12)(13)(14).Aberrant splicing is the basis of many human diseases and up to one-third of disease-causing mutations may lead to splicing defects (15). Although the majority of these defects occur in U2-type introns and splicing factors, perturbations in U12-type splicing have also been described.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Minor class splicing shapes the zebrafish transcriptome during development

Markmiller

Cloonan

Lardelli

et al. 2014

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

View full text Add to dashboard Cite

Minor class or U12-type splicing is a highly conserved process required to remove a minute fraction of introns from human premRNAs. Defects in this splicing pathway have recently been linked to human disease, including a severe developmental disorder encompassing brain and skeletal abnormalities known as Taybi-Linder syndrome or microcephalic osteodysplastic primordial dwarfism 1, and a hereditary intestinal polyposis condition, Peutz-Jeghers syndrome. Although a key mechanism for regulating gene expression, the impact of impaired U12-type splicing on the transcriptome is unknown. Here, we describe a unique zebrafish mutant, caliban (clbn), with arrested development of the digestive organs caused by an ethylnitrosourea-induced recessive lethal point mutation in the rnpc3 [RNA-binding region (RNP1, RRM) containing 3] gene. rnpc3 encodes the zebrafish ortholog of human RNPC3, also known as the U11/U12 di-snRNP 65-kDa protein, a unique component of the U12-type spliceosome. The biochemical impact of the mutation in clbn is the formation of aberrant U11-and U12-containing small nuclear ribonucleoproteins that impair the efficiency of U12-type splicing. Using RNA sequencing and microarrays, we show that multiple genes involved in various steps of mRNA processing, including transcription, splicing, and nuclear export are disrupted in clbn, either through intron retention or differential gene expression. Thus, clbn provides a useful and specific model of aberrant U12-type splicing in vivo. Analysis of its transcriptome reveals efficient mRNA processing as a critical process for the growth and proliferation of cells during vertebrate development.S plicing, the excision of introns from pre-mRNA, is an essential step in gene expression and a major source of complexity in the transcriptome (1). The process is catalyzed by highly dynamic complexes of small nuclear ribonucleoproteins (snRNPs) called spliceosomes (2). Not widely appreciated is the coexistence of two types of introns in most eukaryotic genomes. The vast majority, the major class or U2-type introns, are marked by GT and AG at their 5′ and 3′ ends, respectively. Minor class or U12-type introns, of which there are ∼700 in the human genome, were initially recognized by the presence of AT and AC in these positions, prompting their original name of AT-AC introns (3). However, we now know that most of these introns contain the same GT-AG termini found in U2-type introns (4, 5) and are instead distinguished from them by two highly conserved motifs: one adjacent to the 5′ splice site (ss) and one corresponding to the branch point sequence (BPS), close to the 3′ ss (6, 7). These introns also lack the 3′ polypyrimidine tract characteristic of U2-type introns. Minor class introns are excised by U12-type spliceosomes, which are analogous in function and similar in composition to U2-type spliceosomes; each comprise five small nuclear RNAs (snRNAs) and hundreds of associated proteins (6). Although the U5 snRNA is shared between the two complexes, the U12-type spliceosome con...

show abstract

Section: Rnpc3 Deficiency Leads To a Pleiotropic Phenotype In Developingmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Minor class splicing shapes the zebrafish transcriptome during development

Markmiller

Cloonan

Lardelli

et al. 2014

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

View full text Add to dashboard Cite

show abstract

“…In this regard, it is known that retention of a minor class intron generally leads to degradation of the transcript. 17 The reason for the existence of 2 different spliceosomes is not entirely understood, but it has been suggested that the minor spliceosome acts in the cytoplasm to avoid dependence on a functioning nucleus. This has 1 major advantage; when during cell division, the nuclear envelope breaks down, minor splicing is still available.…”

mentioning

confidence: 99%

“…19 Interestingly, it was recently shown that usage of the minor spliceosome is rapidly increased by the activation of cell-stress activated kinase p38 mitogen-activated protein kinase (MAPK) through stabilization of U6atac. 17 This resulted in increased expression of hundreds of minor intron-containing genes. Because mRNAs with retained minor introns are often degraded through the nonsense-mediated decay (NMD) pathway (Figure 2A), the activation of p38 MAPK may trigger minor spliceosome usage and thus control gene expression in response to stress.…”

mentioning

confidence: 99%

RNA Splicing

Hoogenhof

Pinto

Creemers

2016

Circulation Research

View full text Add to dashboard Cite

RNA splicing, a post-transcriptional process necessary to form a mature mRNA, was discovered in the late 1970s. 1 Two different modes of splicing have been defined, that is, constitutive splicing and alternative splicing. Constitutive splicing is the process of removing introns from the premRNA, and joining the exons together to form a mature mRNA. Alternative splicing, on the other hand, is the process where exons can be included or excluded in different combinations to create a diverse array of mRNA transcripts from a single pre-mRNA and therefore serves as a process to increase the diversity of the transcriptome. The estimated number of alternative splicing events in the human transcriptome has risen sharply over the past decades. In the 1980s, it was thought that about 5% of human genes were subjected to alternative splicing.2 In 2002, this number had risen to 60%, 3 and now, after implementation of next-generation-sequencing technologies, we know that the vast majority, >95% of mRNAs, are subjected to alternative splicing. 4 Nevertheless, the function of a large fraction of these splice isoforms remains to be elucidated. Furthermore, it is anticipated that in different tissues, or in tissues with different disease states, new isoforms still remain to be identified. 5The process of splicing is highly conserved during evolution. Splicing is more prevalent in multicellular than in unicellular eukaryotes because of the lower number of introncontaining genes in the latter. 6 Later in evolution, alternative splicing becomes more prevalent in vertebrates than in invertebrates. Interestingly, just a single exon-skipping event in the RNA-binding protein (RBP), polypyrimidine tract binding protein 1 has been shown to direct numerous alternative splicing changes between species, indicating that a single splicing event can amplify transcriptome diversity between species. 7The recent observation that the total number of protein-coding genes does not differ much between species, fueled the hypothesis that alternative splicing largely contributes to organism diversity. And indeed, as we move up the phylogenetic tree, alternative splicing complexity increases, with the highest complexity in primates. 8,9The aim of this review is to give a comprehensive overview of all aspects of constitutive and alternative splicing and their regulators, as well as the importance of these different aspects in human disease, with a focus on the heart. In addition, we discuss possible therapeutic interventions and try to uncover potential future directions of research. Major and Minor SpliceosomeRNA splicing is performed by the spliceosome, a large and dynamic ribonucleoprotein complex composed of proteins and small nuclear RNAs (snRNAs), which assembles on the pre-mRNA (Figure 1). Ribonucleoproteins consist of 1 or 2 small nuclear RNAs (snRNAs; U1, U2, U4/U6, or U5), and a variable number of complex-specific proteins.

show abstract

Minor splicing snRNAs are enriched in the developing mouse CNS and are crucial for survival of differentiating retinal neurons

Baumgartner

Lemoine

Seesi

et al. 2014

Developmental Neurobiology

View full text Add to dashboard Cite

In eukaryotes, gene expression requires splicing, which starts with the identification of exon-intron boundaries by the small, nuclear RNA (snRNAs) of the spliceosome, aided by associated proteins. In the mammalian genome, <1% of introns lack canonical exon-intron boundary sequences and cannot be spliced by the canonical splicing machinery. These introns are spliced by the minor spliceosome, consisting of unique snRNAs (U11, U12, U4atac, and U6atac). The importance of the minor spliceosome is underscored by the disease microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), which is caused by mutation in U4atac. Thus, it is important to understand the expression and function of the minor spliceosome and its targets in mammalian development, for which we used the mouse as our model. Here, we report enrichment of the minor snRNAs in the developing head/central nervous system (CNS) between E9.5 and E12.5, along with enrichment of these snRNAs in differentiating retinal neurons. Moreover, dynamic expression kinetics of minor intron-containing genes (MIGs) was observed across retinal development. DAVID analysis of MIGs that were cotranscriptionally upregulated embryonically revealed enrichment for RNA metabolism and cell cycle regulation. In contrast, MIGs that were cotranscriptionally upregulated postnatally revealed enrichment for protein localization/transport, vesicle-mediated transport, and calcium transport. Finally, we used U12 morpholino to inactivate the minor spliceosome in the postnatal retina, which resulted in apoptosis of differentiating retinal neurons. Taken together, our data suggest that the minor spliceosome may have distinct functions in embryonic versus postnatal development. Importantly, we show that the minor spliceosome is crucial for the survival of terminally differentiating retinal neurons.

show abstract

Minor introns are embedded molecular switches regulated by highly unstable U6atac snRNA

Cited by 81 publications

References 47 publications

Minor class splicing shapes the zebrafish transcriptome during development

Minor class splicing shapes the zebrafish transcriptome during development

RNA Splicing

Minor splicing snRNAs are enriched in the developing mouse CNS and are crucial for survival of differentiating retinal neurons

Contact Info

Product

Resources

About