Tissue-specific splicing factor gene expression signatures

Grosso, Ana Rita; Gomes, Anita Quintal; Barbosa‐Morais, Nuno L.; Caldeira, Sandra; Thorne, Natalie; Grech, Godfrey; Lindern, Marieke von; Carmo‐Fonseca, Maria

doi:10.1093/nar/gkn463

Cited by 161 publications

(138 citation statements)

References 65 publications

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“…However, exon 1L-containing transcripts in testis may differ from the respective liver transcripts as NCBI dbEST entry BX105309 indicates another exon upstream of exon 1L. Testis and brain express the largest amount of variant transcripts (51). Although exon 1L is not expressed in human brain, we identified two major variant brain transcripts initiated from promoters distinct from the liver-specific promoter.…”

Section: Discussionmentioning

confidence: 87%

Characterization of Novel Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Isoform in Human Liver

Felder

Soyal

Oberkofler

et al. 2011

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) is a transcriptional coactivator that contributes to the regulation of numerous transcriptional programs including the hepatic response to fasting. Mechanisms at transcriptional and post-transcriptional levels allow PGC-1␣ to support distinct biological pathways. Here we describe a novel human liver-specific PGC-1␣ transcript that results from alternative promoter usage and is induced by FOXO1 as well as glucocorticoids and cAMP-response element-binding protein signaling but is not present in other mammals. Hepatic tissue levels of novel and wild-type transcripts were similar but were only moderately associated (p < 0.003). Novel mRNA levels were associated with a polymorphism located in its promoter region, whereas wildtype transcript levels were not. Furthermore, hepatic PCK1 mRNA levels exhibited stronger associations with the novel than with the wild-type transcript levels. Except for a deletion of 127 amino acids at the N terminus, the protein, termed L-PGC-1␣, is identical to PGC-1␣. L-PGC-1␣ was localized in the nucleus and showed coactivation properties that overlap with those of PGC-1␣. Collectively, our data support a role of L-PGC-1␣ in gluconeogenesis, but functional differences predicted from the altered structure suggest that L-PGC-1␣ may have arisen to adapt PGC-1␣ to more complex metabolic pathways in humans. PGC-1␣2 (PPARGC1A) influences transcription in an exceptional variety of biological pathways including adaptive thermogenesis (1), mitochondrial biogenesis (2), skeletal muscle fiber determination and neuromuscular junction formation (3, 4), angiogenesis (5, 6), hepatic gluconeogenesis (7-9), fatty acid ␤-oxidation (10), regulation of clock genes (11), and protection of neural cells from reactive oxygen species (12, 13). Recent reviews describe the numerous functions of this fascinating protein (14 -17).Several levels of regulation have been implicated to explain the diverse roles of PGC-1␣ and its interactions with distinct transcription factors. For some pathways, expression levels of PGC-1␣ and transcription factors coactivated by PGC-1␣ are crucial (18). In addition, various signaling pathways target PGC-1␣ at the post-translational level. Such modifications detailed recently (19) alter the stability of PGC-1␣ and/or direct interactions with specific factors, thereby enhancing distinct transcriptional programs.Alternative splicing and/or transcription initiation, resulting in gain or deletion of interacting domains or signaling targets, represents another mode of regulation (15). Several PGC-1␣ isoforms have been reported in animal models (20,21). A short PGC-1␣ isoform was shown to be coexpressed with wild-type PGC-1␣ in mouse tissues and in human heart (22). The alternatively spliced mRNA is translated into a truncated protein, termed NT-PGC-1␣, that retains the N-terminal transactivation and nuclear receptor interaction domains and is functionally active.Knowledge about PGC-1␣ expression and regulation in human tissu...

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Section: Discussionmentioning

confidence: 87%

Characterization of Novel Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Isoform in Human Liver

Felder

Soyal

Oberkofler

et al. 2011

Journal of Biological Chemistry

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“…The different splicing patterns between fibroblasts, precursor B cells, mature B cells, T cells and NK cells might be caused by cell type and tissue-specific patterns of alternative splicing. 36,37 However, differences in the various B-cell subsets might also reflect positive selection of a limited number of precursor B-cell clones that had a higher Artemis expression and were therefore able to generate a functional B-cell receptor and differentiate into mature B cells.…”

Section: Discussionmentioning

confidence: 99%

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

IJspeert

Lankester

et al. 2011

Genes Immun

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Artemis deficiency is known to result in classical TÀBÀ severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical TÀBÀ SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5 0 splice-site or an intronic point mutation creating a novel 3 0 splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3 0 splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

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“…A similar survey from Drosophila F1 hybrid head tissue reported 65 genes showing cis-acting differences in alternative isoform expression (Graze et al 2012) Results from other studies suggest that changes in the activity or abundance of trans-acting factors may contribute to divergent splicing. The expression levels of splicing regulatory proteins vary between species, suggesting trans-acting network changes (Grosso et al 2008). In addition, the SR and hnRNP families of splicing regulatory proteins have evolved through numerous duplication and divergence events, highlighting the potential for transregulatory changes in splicing regulatory networks .…”

mentioning

confidence: 99%

Evolution of splicing regulatory networks in Drosophila

et al. 2014

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The proteome expanding effects of alternative pre-mRNA splicing have had a profound impact on eukaryotic evolution. The events that create this diversity can be placed into four major classes: exon skipping, intron retention, alternative 59 splice sites, and alternative 39 splice sites. Although the regulatory mechanisms and evolutionary pressures among alternative splicing classes clearly differ, how these differences affect the evolution of splicing regulation remains poorly characterized. We used RNA-seq to investigate splicing differences in D. simulans, D. sechellia, and three strains of D. melanogaster. Regulation of exon skipping and tandem alternative 39 splice sites (NAGNAGs) were more divergent than other splicing classes. Splicing regulation was most divergent in frame-preserving events and events in noncoding regions. We further determined the contributions of cis-and trans-acting changes in splicing regulatory networks by comparing allele-specific splicing in F1 interspecific hybrids, because differences in allele-specific splicing reflect changes in cis-regulatory element activity. We find that species-specific differences in intron retention and alternative splice site usage are primarily attributable to changes in cis-regulatory elements (median~80% cis), whereas species-specific exon skipping differences are driven by both cis-and trans-regulatory divergence (median~50% cis). These results help define the mechanisms and constraints that influence splicing regulatory evolution and show that networks regulating the four major classes of alternative splicing diverge through different genetic mechanisms. We propose a model in which differences in regulatory network architecture among classes of alternative splicing affect the evolution of splicing regulation.

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Tissue-specific splicing factor gene expression signatures

Cited by 161 publications

References 65 publications

Characterization of Novel Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Isoform in Human Liver

Characterization of Novel Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Isoform in Human Liver

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Evolution of splicing regulatory networks in Drosophila

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