scholarly journals Evidence from Amphioxus for acquisition of alternative mRNA splicing of NCoR corepressor after its duplication and divergence during vertebrate evolution

2020 ◽  
Author(s):  
Martin L. Privalsky
Keyword(s):  
Alternative Splicing ◽  
Gene Duplication ◽  
Duplication Event ◽  
Mrna Splicing ◽  
Vertebrate Evolution ◽  
Divergent Evolution ◽  
Vertebrate Lineage ◽  
Selective Pressures ◽  
Alternative Mrna Splicing ◽  
Transcriptional Corepressors

ABSTRACTNCoR-1 and NCoR-2 are transcriptional corepressors encoded in vertebrates by two interrelated loci and play distinct, though overlapping, roles in development, differentiation, and homeostasis. In contrast NCoR is encoded by a single locus in cephalochordates, urochordates, hemichordates, and echinoderms, with vertebrate NCoR-1 and NCoR-2 thought to be the products of a gene duplication originating near the beginning of vertebrate evolution. The structures, molecular properties, and functions of extant NCoR-1 and NCoR-2 are each substantially further diversified by alternative mRNA splicing; however it is unresolved as to whether the alternative-splicing observed in current day vertebrates reflects patterns present in the ancestral common gene or instead arose after the NCoR duplication event. This manuscript reports that Amphioxus, a cephalochordate considered representative of the organisms that gave rise to the vertebrate lineage, lacks the alternative NCoR splicing events characteristic of vertebrates. This, together with prior taxonomic comparisons, suggests that the patterns of corepressor splicing found in existing vertebrates arose exclusively after the NCoR duplication event. Further, given that alternative-splicing of NCoR-1 and NCoR-2 appears to have arisen by a mix of convergent and divergent evolution, it is likely that both common and distinct selective pressures were operative on these corepressor paralogs after their divergence.

scholarly journals Identification of a Novel Estrogen Receptor-α Variant and Its Upstream Splicing Regulator

2010 ◽  
Vol 24 (5) ◽  
pp. 914-922 ◽  
Author(s):  
Kazufumi Ohshiro ◽  
Prakriti Mudvari ◽  
Qing-chang Meng ◽  
Suresh K. Rayala ◽  
Aysegul A. Sahin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Alternative Splicing ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Estrogen Receptor Α ◽  
Mrna Splicing ◽  
Human Breast ◽  
Alternative Mrna Splicing

Abstract Alternative splicing of precursor mRNA is a fundamental mechanism to generate multiple proteins from a single gene. Although constitutive and alternative mRNA splicing is temporally and spatially regulated, deregulation of mRNA splicing could cause development, progression, and metastasis of tumors. Through yeast two-hybrid screening of a human breast cDNA library using estrogen receptor-α (ERα) as bait, we identified a novel nuclear receptor box containing full-length protein, nuclear protein E3-3 (NPE3-3). Our results revealed that NPE3-3 associates with not only ERα but also with splicing factors, serine/arginine-rich protein (SRp)-30c, SRp40, and splicing factor SC-35, suggesting that NPE3-3 is likely to be involved in regulation of mRNA splicing. Accordingly, transient expression of NPE3-3 in cells resulted in expected splicing of the CD44 control minigene. We also discovered that NPE3-3-overexpressing clones produced a novel, previously unrecognized, alternatively spliced variant of ERα (termed ERαV), which had a molecular size of 37 kDa composed of only exons 1, 2, 7, and 8. ERαV was expressed and sequestered in the cytoplasm in MCF-7 cells stably overexpressing NPE3-3, suggesting its involvement in nongenomic hormone signaling. NPE3-3 clones exhibited up-regulation of ERK1/2 signaling, cyclin D1, and cathepsin D and enhanced tumor cell proliferation, migration, and tumorigenicity. Moreover, direct expression of the ERαV in breast cancer cells stimulated ERK1/2 up-regulation and cyclin D1 expression. We found that ERαV physically interacted with MAPK kinase (MEK)-1/2, and thus, an ERαV and MEK1/2 complex could lead to the activation of the ERK1/2 pathway. Interestingly, NPE3-3 was up-regulated in human breast tumors. These findings revealed a role for NPE3-3 in alternative splicing and suggest that ERα is a physiological target of NPE3-3, leading to a constitutive nongenomic signaling pathway in breast cancer cells.

scholarly journals MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1818
Author(s):  
Rahaba Marima ◽  
Flavia Zita Francies ◽  
Rodney Hull ◽  
Thulo Molefi ◽  
Meryl Oyomno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Alternative Splicing ◽  
Mirna Expression ◽  
Drug Targets ◽  
Mrna Splicing ◽  
Cancer Drug ◽  
Aberrant Splicing ◽  
Cancer Drug Resistance ◽  
Alternative Mrna Splicing

Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression. Alternative splicing increases the diversity of the proteome by producing several different spliced mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia. Alternative splicing may change the target mRNA 3′UTR binding site. This alteration can affect the produced protein and may ultimately affect the drug affinity of target proteins, eventually leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The interplay between miRNA and alternative splicing is largely due to splicing resulting in altered 3′UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug resistance poses a substantial challenge in the management of the disease. Henceforth, molecular alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. While the miRNA–mRNA splicing interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in deciphering miRNA-mediated drug resistance.

Abstract 235: Global RNA Splicing and Regulation in Cardiac Maturation and Diseases

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
CHEN GAO ◽  
Vincent Ren ◽  
Jae-Hyung Lee ◽  
Xinshu (Grace) Xiao ◽  
Jau-nian Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Alternative Splicing ◽  
Cardiac Function ◽  
Rna Splicing ◽  
Cardiac Development ◽  
Mrna Splicing ◽  
Pcr Analysis ◽  
Mouse Heart ◽  
Global Pattern ◽  
Alternative Mrna Splicing

Background: The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is also implicated in many human diseases including cancer. However, the global pattern of alternative mRNA splicing during cardiac development and diseases is unknown, and the regulatory mechanisms remain unexplored. Methods and Results: Using deep RNA-Sequencing, we have identified global alternative splicing changes associated with both cardiac development and pathological remodeling in mouse heart following pressure-overload induced heart failure. The alternative RNA splicing events observed in failing hearts mimics the profile in fetal hearts, suggesting a fetal-like RNA splicing program induced in diseased hearts. Using RNA-Seq database and real-time PCR analysis, we examined the expression profile of a large number of known alternative splicing regulators. Among them, we identified Fox1 as a significantly induced regulator during cardiac development in zebrafish, mouse and human, and down-regulated in both mouse and human failing hearts. Morpholino mediated Fox1 knockdown in zebrafish embryos led to lethal phenotype associated with reduced cardiac function and defects in chamber specificity. This phenotype could be rescued by re-expressing both zebrafish and mouse Fox1 gene, suggesting a highly conserved cardiac function of Fox1 for normal cardiac development and function in vertebrates. Conclusion: Our study provided the first comprehensive analysis of mRNA splicing regulation in heart during post-natal development and heart failure, and identified Fox1 as a key regulator for alternative RNA splicing in heart. This study expands our current understanding to the complexity of cardiac transcriptome, and reveals the functional importance of RNA-splicing in cardiac development and diseases.

scholarly journals CtIP -mediated alternative mRNA splicing finetunes the DNA damage response

2019 ◽  
Author(s):  
Rosario Prados-Carvajal ◽  
Guillermo Rodríguez-Real ◽  
Gabriel Gutierrez-Pozo ◽  
Pablo Huertas
Keyword(s):  
Dna Damage ◽  
Alternative Splicing ◽  
Dna Damage Response ◽  
Active Form ◽  
Mrna Splicing ◽  
Global Changes ◽  
Dna Damaging Agents ◽  
Alternative Mrna Splicing ◽  
Damage Response ◽  
In Cells

AbstractIn order to survive to the exposure of DNA damaging agents, cells activate a complex response that coordinates the cellular metabolism, cell cycle progression and DNA repair. Among many other events, recent evidence has described global changes in mRNA splicing in cells treated with genotoxic agents. Here, we explore further this DNA damage-dependent alternative splicing. Indeed, we show that both the splicing factor SF3B2 and the repair protein CtIP contribute to the global pattern of splicing both in cells treated or not to DNA damaging agents. Additionally, we focus on a specific DNA damage- and CtIP-dependent alternative splicing event of the helicase PIF1 and explore its relevance for the survival of cells upon exposure to ionizing radiation. Indeed, we described how the nuclear, active form of PIF1 is substituted by a splicing variant, named vPIF1, in a fashion that requires both the presence of DNA damage and CtIP. Interestingly, timely expression of vPIF1 is required for optimal survival to exposure to DNA damaging agents, but early expression of this isoform delays early events of the DNA damage response. On the contrary, expression of the full length PIF1 facilitates those early events, but increases the sensitivity to DNA damaging agents if the expression is maintained long-term.

scholarly journals Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds

2020 ◽  
Vol 21 (6) ◽  
pp. 2026
Author(s):  
Ken-ichi Fujita ◽  
Takaki Ishizuka ◽  
Mizuki Mitsukawa ◽  
Masashi Kurata ◽  
Seiji Masuda
Keyword(s):  
Alternative Splicing ◽  
Messenger Rna ◽  
Basic Research ◽  
Mrna Splicing ◽  
Rna Structures ◽  
Anticancer Effects ◽  
Isoform Diversity ◽  
Alternative Mrna Splicing ◽  
Biological Tool ◽  
Clinical Potential

Human transcriptomes are more divergent than genes and contribute to the sophistication of life. This divergence is derived from various isoforms arising from alternative splicing. In addition, alternative splicing regulated by spliceosomal factors and RNA structures, such as the RNA G-quadruplex, is important not only for isoform diversity but also for regulating gene expression. Therefore, abnormal splicing leads to serious diseases such as cancer and neurodegenerative disorders. In the first part of this review, we describe the regulation of divergent transcriptomes using alternative mRNA splicing. In the second part, we present the relationship between the disruption of splicing and diseases. Recently, various compounds with splicing inhibitor activity were established. These splicing inhibitors are recognized as a biological tool to investigate the molecular mechanism of splicing and as a potential therapeutic agent for cancer treatment. Food-derived compounds with similar functions were found and are expected to exhibit anticancer effects. In the final part, we describe the compounds that modulate the messenger RNA (mRNA) splicing process and their availability for basic research and future clinical potential.

Abstract 15: Global RNA Splicing Regulation in Cardiac Maturation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Chen Gao ◽  
Shuxun Ren ◽  
Jae-Hyung Lee ◽  
Yun-Hua Esther Hsiao ◽  
Xinshu (Grace) Xiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Sequencing ◽  
Rna Splicing ◽  
Mrna Splicing ◽  
Splicing Regulation ◽  
Sequencing Analysis ◽  
Cell Based Therapy ◽  
Alternative Mrna Splicing ◽  
Cardiac Maturation

Background: The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is implicated in both development and disease. However, the change of alternative mRNA splicing during cardiomyocytes maturation is unknown, and the regulatory mechanisms remain unexplored. Methods and Results: Using deep RNA-Sequencing, we identified global alternative splicing changes associated with both cardiac development and pathological remodeling in mouse heart. Further, we identified a highly conserved splicing regulator-RBFox1 to be significantly induced during zebrafish, mouse and human cardiac maturation. RBFox1 expression was also detected in cardiomyocytes derived from both mouse and human embryonic stem cells but at much lower levels comparing to adult heart. In zebrafish embryos, inactivation of RBFox1 caused cardiomyocyte maturation defects. Expression of RBFox1 in cultured neonatal cardiomyocytes was sufficient to promote maturation by reducing fetal marker gene expression while increasing calcium handling gene expression including RyR and promoting sarcomere organization. Deep RNA-Sequencing analysis showed that RBFox1 expression promoted alternative splicing in genes involved in calcium cycling, blood vessel development and muscle contraction. Finally, we identified a highly conserved mutually exclusive alternative splicing event of transcription factor MEF2 to be a direct downstream target of RBFox1. Expression of individual MEF2 splicing variants led to different cardiac developmental phenotypes in zebrafish, indicating their different transcriptional activities. Conclusion: Our study provided the first comprehensive analysis of mRNA splicing regulation in heart during post-natal development and heart failure, and identified RBFox1 as a key regulator for alternative RNA splicing during cardiomyocytes maturation. Further exploration of RBFox1 mediated RNA splicing regulation in heart may yield novel insight to the underlying mechanisms of cardiac maturation and new approach to improve cell based therapy for heart diseases.

scholarly journals The divergence of alternative splicing between ohnologs in teleost fishes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuwei Wang ◽  
Baocheng Guo
Keyword(s):  
Alternative Splicing ◽  
Gene Duplication ◽  
Functional Divergence ◽  
Duplication Event ◽  
Rna Seq ◽  
Genome Duplication Event ◽  
Duplication Events ◽  
Function Sharing ◽  
Independent Model ◽  
Rule Out

Abstract Background Gene duplication and alternative splicing (AS) are two distinct mechanisms generating new materials for genetic innovations. The evolutionary link between gene duplication and AS is still controversial, due to utilizing duplicates from inconsistent ages of duplication events in earlier studies. With the aid of RNA-seq data, we explored evolutionary scenario of AS divergence between duplicates with ohnologs that resulted from the teleost genome duplication event in zebrafish, medaka, and stickleback. Results Ohnologs in zebrafish have fewer AS forms compared to their singleton orthologs, supporting the function-sharing model of AS divergence between duplicates. Ohnologs in stickleback have more AS forms compared to their singleton orthologs, which supports the accelerated model of AS divergence between duplicates. The evolution of AS in ohnologs in medaka supports a combined scenario of the function-sharing and the accelerated model of AS divergence between duplicates. We also found a small number of ohnolog pairs in each of the three teleosts showed significantly asymmetric AS divergence. For example, the well-known ovary-factor gene cyp19a1a has no AS form but its ohnolog cyp19a1b has multiple AS forms in medaka, suggesting that functional divergence between duplicates might have result from AS divergence. Conclusions We found that a combined scenario of function-sharing and accelerated models for AS evolution in ohnologs in teleosts and rule out the independent model that assumes a lack of correlation between gene duplication and AS. Our study thus provided insights into the link between gene duplication and AS in general and ohnolog divergence in teleosts from AS perspective in particular.

scholarly journals Genome-wide Analysis of Alternative Pre-mRNA Splicing

2007 ◽  
Vol 283 (3) ◽  
pp. 1229-1233 ◽  
Author(s):  
Claudia Ben-Dov ◽  
Britta Hartmann ◽  
Josefin Lundgren ◽  
Juan Valcárcel
Keyword(s):  
Alternative Splicing ◽  
Large Scale ◽  
Mrna Splicing ◽  
Diagnostic Tools ◽  
Primary Transcript ◽  
Genome Wide ◽  
Human Genes ◽  
Multicellular Organisms ◽  
Eukaryotic Genomes ◽  
Key Questions

Alternative splicing of mRNA precursors allows the synthesis of multiple mRNAs from a single primary transcript, significantly expanding the information content and regulatory possibilities of higher eukaryotic genomes. High-throughput enabling technologies, particularly large-scale sequencing and splicing-sensitive microarrays, are providing unprecedented opportunities to address key questions in this field. The picture emerging from these pioneering studies is that alternative splicing affects most human genes and a significant fraction of the genes in other multicellular organisms, with the potential to greatly influence the evolution of complex genomes. A combinatorial code of regulatory signals and factors can deploy physiologically coherent programs of alternative splicing that are distinct from those regulated at other steps of gene expression. Pre-mRNA splicing and its regulation play important roles in human pathologies, and genome-wide analyses in this area are paving the way for improved diagnostic tools and for the identification of novel and more specific pharmaceutical targets.

scholarly journals Versican gene expression in human articular cartilage and comparison of mRNA splicing variation with aggrecan

1993 ◽  
Vol 291 (2) ◽  
pp. 361-367 ◽  
Author(s):  
J Grover ◽  
P J Roughley
Keyword(s):  
Alternative Splicing ◽  
Articular Cartilage ◽  
Regulatory Protein ◽  
Mrna Splicing ◽  
Human Articular Cartilage ◽  
Complement Regulatory Protein ◽  
Mature Adult ◽  
Epidermal Growth ◽  
Egf Domain

The chondrocytes in human articular cartilage from subjects of all ages express mRNAs for both of the aggregating proteoglycans aggrecan and versican, although the level of expression of versican mRNA is much lower than that of aggrecan mRNA. Aggrecan shows alternative splicing of the epidermal growth factor (EGF)-like domain within its C-terminal globular region, but there is no evidence for a major difference in situ in the relative expression of this domain with age. At all ages studied from birth to the mature adult, a greater proportion of transcripts lacked the EGF domain. The relative proportions of the two transcripts did not change upon culture and passage of isolated chondrocytes. In contrast, the neighbouring complement regulatory protein (CRP)-like domain was predominantly expressed irrespective of age, but cell culture did result in variation of the splicing of this domain. Versican possesses two EGF-like domains and one CRP-like domain, but at all ages the three domains were predominantly present in all transcripts. This situation persisted upon culture and passage of the chondrocytes. Thus, unlike aggrecan, the versican expressed by human articular cartilage does not appear to undergo alternative splicing of its C-terminal globular region, either in cartilage in situ or in chondrocytes in culture.

scholarly journals Identification of members of the P-glycoprotein multigene family.

1989 ◽  
Vol 9 (3) ◽  
pp. 1224-1232 ◽  
Author(s):  
W F Ng ◽  
F Sarangi ◽  
R L Zastawny ◽  
L Veinot-Drebot ◽  
V Ling
Keyword(s):  
Multidrug Resistance ◽  
Gene Duplication ◽  
Gene Family ◽  
Multigene Family ◽  
Rhesus Monkeys ◽  
Genomic Library ◽  
Duplication Event ◽  
Glycoprotein Gene ◽  
P Glycoprotein ◽  
Exon Probe

Overproduction of P-glycoprotein is intimately associated with multidrug resistance. This protein appears to be encoded by a multigene family. Thus, differential expression of different members of this family may contribute to the complexity of the multidrug resistance phenotype. Three lambda genomic clones isolated from a hamster genomic library represent different members of the hamster P-glycoprotein gene family. Using a highly conserved exon probe, we found that the hamster P-glycoprotein gene family consists of three genes. We also found that the P-glycoprotein gene family consists of three genes in mice but has only two genes in humans and rhesus monkeys. The hamster P-glycoprotein genes have similar exon-intron organizations within the 3' region encoding the cytoplasmic domains. We propose that the hamster P-glycoprotein gene family arose from gene duplication. The hamster pgp1 and pgp2 genes appear to be more closely related to each other than either gene is to the pgp3 gene. We speculate that the hamster pgp1 and pgp2 genes arose from a recent gene duplication event and that primates did not undergo this duplication and therefore contain only two P-glycoprotein genes.

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