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1.
Adv Exp Med Biol ; 1164: 119-139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576545

RESUMO

Alternative splicing, the process of removing introns and joining exons of pre-mRNA, is critical for growth, development, tissue homeostasis, and species diversity. Dysregulation of alternative splicing can initiate and drive disease. Aberrant alternative splicing has been shown to promote the "hallmarks of cancer" in both hematological and solid cancers. Of interest, recent work has focused on the role of alternative splicing in prostate cancer and prostate cancer health disparities. We will provide a review of prostate cancer health disparities involving the African American population, alternative RNA splicing, and alternative splicing in prostate cancer. Lastly, we will summarize our work on differential alternative splicing in prostate cancer disparities and its implications for disparate health outcomes and therapeutic targets.


Assuntos
Processamento Alternativo , Resistência a Medicamentos , Disparidades nos Níveis de Saúde , Neoplasias da Próstata , Afro-Americanos/estatística & dados numéricos , Processamento Alternativo/genética , Resistência a Medicamentos/genética , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/fisiopatologia
2.
Biomed Khim ; 65(4): 263-276, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31436168

RESUMO

Protein p53 is one of the most studied proteins. This attention is primarily due to its key role in the cellular mechanisms associated with carcinogenesis. Protein p53 is a transcription factor involved in a wide variety of processes: cell cycle regulation and apoptosis, signaling inside the cell, DNA repair, coordination of metabolic processes, regulation of cell interactions, etc. This multifunctionality is apparently determined by the fact that p53 is a vivid example of how the same protein can be represented by numerous proteoforms bearing completely different functional loads. By alternative splicing, using different promoters and translation initiation sites, the TP53 gene gives rise to at least 12 isoforms, which can additionally undergo numerous (>200) post-translational modifications. Proteoforms generated due to numerous point mutations in the TP53 gene are adding more complexity to this picture. The proteoforms produced are involved in various processes, such as the regulation of p53 transcriptional activity in response to various factors. This review is devoted to the description of the currently known p53 proteoforms, as well as their possible functionality.


Assuntos
Processamento Alternativo , Genes p53 , Proteína Supressora de Tumor p53/química , Humanos , Mutação Puntual , Isoformas de Proteínas/química , Processamento de Proteína Pós-Traducional , Relação Estrutura-Atividade
3.
Gene ; 719: 144075, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31449843

RESUMO

The human L-DOPA decarboxylase (DDC) is a gene that has been in the center of research attention in many laboratories the last decades, due to its major implication in various disorders, including many types of cancer. In the current work, we used in-house developed RACE and high-throughput sequencing approaches, in order to detect and identify novel DDC transcripts. Bioinformatic analysis revealed new alternative splicing events that support the existence of novel DDC transcripts. As a result, a total of 14 DDC splice variants were identified and their expression profile was investigated in a wide panel of human cancer cell lines. From all 14 novel DDC transcripts that were identified, 9 transcripts are predicted to encode new protein isoforms, while the remaining 5 are nonsense-mediated mRNA decay (NMD) candidates. Our results demonstrate that the human DDC gene undergoes complex processing leading to the figuration of multiple mRNA isoforms in cancer cells.


Assuntos
Processamento Alternativo , Descarboxilases de Aminoácido-L-Aromático/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequência de Bases , Linhagem Celular Tumoral , Éxons , Perfilação da Expressão Gênica , Humanos , RNA Mensageiro/genética
4.
BMC Bioinformatics ; 20(1): 421, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409274

RESUMO

BACKGROUND: Ultra-fast pseudo-alignment approaches are the tool of choice in transcript-level RNA sequencing (RNA-seq) analyses. Unfortunately, these methods couple the tasks of pseudo-alignment and transcript quantification. This coupling precludes the direct usage of pseudo-alignment to other expression analyses, including alternative splicing or differential gene expression analysis, without including a non-essential transcript quantification step. RESULTS: In this paper, we introduce a transcriptome segmentation approach to decouple these two tasks. We propose an efficient algorithm to generate maximal disjoint segments given a transcriptome reference library on which ultra-fast pseudo-alignment can be used to produce per-sample segment counts. We show how to apply these maximally unambiguous count statistics in two specific expression analyses - alternative splicing and gene differential expression - without the need of a transcript quantification step. Our experiments based on simulated and experimental data showed that the use of segment counts, like other methods that rely on local coverage statistics, provides an advantage over approaches that rely on transcript quantification in detecting and correctly estimating local splicing in the case of incomplete transcript annotations. CONCLUSIONS: The transcriptome segmentation approach implemented in Yanagi exploits the computational and space efficiency of pseudo-alignment approaches. It significantly expands their applicability and interpretability in a variety of RNA-seq analyses by providing the means to model and capture local coverage variation in these analyses.


Assuntos
Algoritmos , Transcriptoma , Processamento Alternativo , Animais , Área Sob a Curva , Drosophila/genética , Humanos , RNA/química , RNA/metabolismo , Curva ROC , Análise de Sequência de RNA
5.
Yi Chuan ; 41(6): 469-485, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31257196

RESUMO

The field of circular non-coding RNAs have been gradually attracted wide attention with the developments of high-throughput sequencing. In this review, we systematically summarize three driving models for circRNAs biogenesis: intron-pairing-driven, RNA binding protein-driven and lariat-driven. In addition, we also briefly introduce the current research methods of circRNAs, which include high-throughput library construction methods, identification through bioinformatics and common experimental verification. Here, we also systematically summarize the functions of circRNAs, including microRNA (miRNA) or protein sponges, regulating the alternative splicing (AS) and expression of host genes, and extensive translation. Finally, we provide a systematic characterization and the latest research progress of circRNAs, which provide a new perspective for further studies of circRNAs in plants.


Assuntos
Processamento Alternativo , RNA/genética , Íntrons , MicroRNAs , Modelos Genéticos , Plantas/genética , Proteínas de Ligação a RNA
6.
Adv Exp Med Biol ; 1157: 1-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31342435

RESUMO

mRNA processing events introduce an intricate layer of complexity into gene expression processes, supporting a tremendous level of diversification of the genome's coding and regulatory potential, particularly in vertebrate species. The recent development of massive parallel sequencing methods and their adaptation to the identification and quantification of different RNA species and the dynamics of mRNA metabolism and processing has generated an unprecedented view over the regulatory networks that are established at this level, which contribute to sustain developmental, tissue specific or disease specific gene expression programs. In this chapter, we provide an overview of the recent evolution of transcriptome profiling methods and the surprising insights that have emerged in recent years regarding distinct mRNA processing events - from the 5' end to the 3' end of the molecule.


Assuntos
Processamento Alternativo , RNA Mensageiro , Análise de Sequência de RNA , Transcriptoma , Perfilação da Expressão Gênica , RNA Mensageiro/metabolismo
7.
Gene ; 716: 144010, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31352009

RESUMO

Alternative splicing can generate multiple protein messages from a single gene and has emerged as an important mechanism to regulate cancer pathways. The human SAT1 gene produces two transcript variants: one translates spermidine/spermine N-1 acetyltransferase (SSAT1), the rate-limiting enzyme in the catabolism of polyamines, and the other generates SSATX, which has largely unknown biological functions. Here, we used experimental data and analyses of several melanoma transcriptome datasets to reveal that SSATX is weakly expressed in melanoma cells. SSATX knockdown promoted the proliferation, migration, and invasion of human melanoma cells via the activation of the Wnt signaling pathway in a manner that was independent of SSAT1 expression. Based on our data, we propose that SSATX functions as a long non-coding RNA prior to its degradation in melanoma cells. Overall, our findings indicate that SSATX acts as a tumor suppressor, which may aid the future diagnosis and treatment of melanoma.


Assuntos
Melanoma/genética , RNA Longo não Codificante/fisiologia , Acetiltransferases/genética , Processamento Alternativo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Melanoma/metabolismo , Melanoma/patologia , Invasividade Neoplásica , RNA Longo não Codificante/genética , Via de Sinalização Wnt
8.
Zool Res ; 40(4): 293-304, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31271004

RESUMO

Divergence of gene expression and alternative splicing is a crucial driving force in the evolution of species; to date, however the molecular mechanism remains unclear. Hybrids of closely related species provide a suitable model to analyze allele-specific expression (ASE) and allele-specific alternative splicing (ASS). Analysis of ASE and ASS can uncover the differences in cis-regulatory elements between closely related species, while eliminating interference of trans-regulatory elements. Here, we provide a detailed characterization of ASE and ASS from 19 and 10 transcriptome datasets across five tissues from reciprocal-cross hybrids of horse×donkey (mule/hinny) and cattle×yak (dzo), respectively. Results showed that 4.8%-8.7% and 10.8%-16.7% of genes exhibited ASE and ASS, respectively. Notably, lncRNAs and pseudogenes were more likely to show ASE than protein-coding genes. In addition, genes showing ASE and ASS in mule/hinny were found to be involved in the regulation of muscle strength, whereas those of dzo were involved in high-altitude adaptation. In conclusion, our study demonstrated that exploration of genes showing ASE and ASS in hybrids of closely related species is feasible for species evolution research.


Assuntos
Alelos , Processamento Alternativo , Bovinos/genética , Equidae/genética , Hibridização Genética/genética , Animais , Sequência de Bases , Regulação da Expressão Gênica , RNA/genética , RNA/metabolismo
9.
Anticancer Res ; 39(6): 2811-2819, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177118

RESUMO

BACKGROUND/AIM: Recent knowledge implicates a differential expression of the insulin-like growth factor-I (IGF-I) mRNA splice variants (i.e., IGF-IEa, IGF-IEb and IGF-IEc) in cancerous tissues, implying possible specific roles of the encoded IGF-I protein isoforms in cancer biology. In particular, there is growing evidence that the IGF-IEc isoform may play a distinct biological role in various types of cancers. The present study investigated whether IGF-IEc expression is associated with a particular type of thyroid cancer. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue specimens of different types of thyroid cancers from 92 patients were assessed for IGF-IEc expression by immunohistochemistry. In addition, thyroid cancer biopsies of different TNM staging histological types were evaluated for mRNA expression of the IGF-IEc transcript by real-time polymerase chain reaction (PCR). RESULTS: From the total number of 92 samples, 2 were anaplastic, 10 medullary, 4 hyperplasias of C-cells, 11 follicular, 5 hurtle cell carcinomas, 2 poorly differentiated, 5 nodular hyperplasias, 1 lymphoma and 52 were papillary thyroid cancers. The age of cancer diagnosis or tumor size did not significantly affect the IGF-IEc expression. Among all types of cancers, IGF-IEc was expressed in papillary differentiated thyroid cancer. Its expression/localization was mainly cytoplasmic and significantly associated with TNM staging and the presence of muscular and capsule cancerous invasion (p<0.05). Similarly, a differential profile was revealed regarding the mRNA expression of the IGF-IEc transcript, that exhibited a higher expression in aggressive compared to the non-aggressive papillary cancers. CONCLUSION: IGF-IEc isoform expression in thyroid cancer is positively associated with more advanced stages of papillary thyroid cancer.


Assuntos
Processamento Alternativo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima , Adolescente , Adulto , Idoso , Citoplasma/genética , Citoplasma/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Carga Tumoral , Adulto Jovem
10.
BMC Genomics ; 20(1): 455, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164105

RESUMO

BACKGROUND: Natural rubber, an indispensable commodity used in approximately 40,000 products, is fundamental to the tire industry. The rubber tree species Hevea brasiliensis (Willd. ex Adr. de Juss.) Muell-Arg., which is native the Amazon rainforest, is the major producer of latex worldwide. Rubber tree breeding is time consuming, expensive and requires large field areas. Thus, genetic studies could optimize field evaluations, thereby reducing the time and area required for these experiments. In this work, transcriptome sequencing was used to identify a full set of transcripts and to evaluate the gene expression involved in the different cold-response strategies of the RRIM600 (cold-resistant) and GT1 (cold-tolerant) genotypes. RESULTS: We built a comprehensive transcriptome using multiple database sources, which resulted in 104,738 transcripts clustered in 49,304 genes. The RNA-seq data from the leaf tissues sampled at four different times for each genotype were used to perform a gene-level expression analysis. Differentially expressed genes (DEGs) were identified through pairwise comparisons between the two genotypes for each time series of cold treatments. DEG annotation revealed that RRIM600 and GT1 exhibit different chilling tolerance strategies. To cope with cold stress, the RRIM600 clone upregulates genes promoting stomata closure, photosynthesis inhibition and a more efficient reactive oxygen species (ROS) scavenging system. The transcriptome was also searched for putative molecular markers (single nucleotide polymorphisms (SNPs) and microsatellites) in each genotype. and a total of 27,111 microsatellites and 202,949 (GT1) and 156,395 (RRIM600) SNPs were identified in GT1 and RRIM600. Furthermore, a search for alternative splicing (AS) events identified a total of 20,279 events. CONCLUSIONS: The elucidation of genes involved in different chilling tolerance strategies associated with molecular markers and information regarding AS events provides a powerful tool for further genetic and genomic analyses of rubber tree breeding.


Assuntos
Resposta ao Choque Frio/genética , Hevea/genética , Processamento Alternativo , Perfilação da Expressão Gênica , Marcadores Genéticos , Hevea/metabolismo , Anotação de Sequência Molecular , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Polimorfismo de Nucleotídeo Único , Domínios Proteicos , Análise de Sequência de RNA
11.
BMC Genomics ; 20(1): 456, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170917

RESUMO

BACKGROUND: Ricinus communis is a highly economically valuable oil crop plant from the spurge family, Euphorbiaceae. However, the available reference genomes are incomplete and to date studies on ricinoleic acid biosynthesis at the transcriptional level are limited. RESULTS: In this study, we combined PacBio single-molecule long read isoform and Illumina RNA sequencing to identify the alternative splicing (AS) events, novel isoforms, fusion genes, long non-coding RNAs (lncRNAs) and alternative polyadenylation (APA) sites to unveil the transcriptomic complexity of castor beans and identify critical genes related to ricinoleic acid biosynthesis. Here, we identified 11,285 AS-variants distributed in 21,448 novel genes and detected 520 fusion genes, 320 lncRNAs and 9511 (APA-sites). Furthermore, a total of 6067, 5983 and 4058 differentially expressed genes between developing beans of the R. communis lines 349 and 1115 with extremely different oil content were identified at 7, 14 and 21 days after flowering, respectively. Specifically, 14, 18 and 11 DEGs were annotated encoding key enzymes related to ricinoleic acid biosynthesis reflecting the higher castor oil content of 1115 compared than 349. Quantitative real-time RT-PCR further validated fifteen of these DEGs at three-time points. CONCLUSION: Our results significantly improved the existed gene models of R. communis, and a putative model of key genes was built to show the differences between strains 349 and 1115, illustrating the molecular mechanism of castor oil biosynthesis. A multi-transcriptome database and candidate genes were provided to further improve the level of ricinoleic acid in transgenic crops.


Assuntos
Ácidos Ricinoleicos/metabolismo , Ricinus/genética , Transcriptoma , Processamento Alternativo , Perfilação da Expressão Gênica , Fusão Gênica , Genes de Plantas , Sequenciamento de Nucleotídeos em Larga Escala , Poliadenilação , RNA Longo não Codificante/genética , Ricinus/metabolismo , Análise de Sequência de RNA , Fatores de Transcrição/genética
12.
Nat Commun ; 10(1): 2673, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209208

RESUMO

Alternative splicing performs a central role in expanding genomic coding capacity and proteomic diversity. However, programming of splicing patterns in engineered biological systems remains underused. Synthetic approaches thus far have predominantly focused on controlling expression of a single protein through alternative splicing. Here, we describe a modular and extensible platform for regulating four programmable exons that undergo a mutually exclusive alternative splicing event to generate multiple functionally-distinct proteins. We present an intron framework that enforces the mutual exclusivity of two internal exons and demonstrate a graded series of consensus sequence elements of varying strengths that set the ratio of two mutually exclusive isoforms. We apply this framework to program the DNA-binding domains of modular transcription factors to differentially control downstream gene activation. This splicing platform advances an approach for generating diverse isoforms and can ultimately be applied to program modular proteins and increase coding capacity of synthetic biological systems.


Assuntos
Processamento Alternativo/genética , Regulação da Expressão Gênica/genética , Engenharia Genética/métodos , RNA/genética , Fatores de Transcrição/genética , Motivos de Aminoácidos/genética , Animais , Linhagem Celular , Biologia Computacional , Sequência Consenso/genética , Éxons/genética , Biblioteca Gênica , Genes Reporter/genética , Humanos , Íntrons/genética , Mutagênese Sítio-Dirigida/métodos , Domínios Proteicos/genética , Isoformas de Proteínas/genética , RNA/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética
13.
Plant Mol Biol ; 100(6): 647-658, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154655

RESUMO

KEY MESSAGE: Found a trans-splicing of PHYTOENE SYNTHASE 1 alters tomato fruit color by map-based cloning, functional complementation and RACE providing an insight into fruit color development. Color is an important fruit quality trait and a major determinant of the economic value of tomato (Solanum lycopersicum). Fruit color inheritance in a yellow-fruited cherry tomato (cv. No. 22), named yellow-fruited tomato 2 (yft2), was shown to be controlled by a single recessive gene, YFT2. The YFT2 gene was mapped in a 95.7 kb region on chromosome 3, and the candidate gene, PHYTOENE SYNTHASE 1 (PSY1), was confirmed by functional complementation analysis. Constitutive over expression of PSY1 in yft2 increased the accumulation of carotenoids and resulted in a red fruit color, while no causal mutation was detected in the YFT2 allele of yft2, compared with red-fruited SL1995 cherry tomato or cultivated variety (cv. M82). Expression of YFT2 3' region in yft2 was significantly lower than in SL1995, and further studies revealed a difference in YFT2 post-transcriptional processing in yft2 compared with SL1995 and cv. M82, resulting in a longer YFT2 transcript. The alternatively trans-spliced allele of YFT2 in yft2 is predicted to encode a novel LT-YFT2 protein of 432 amino acid (AA) residues, compared to the 412 AA YFT2 protein of SL1995. The trans-spliced event also resulted in significantly down regulated expression of YFT2 in yft2 tomato, and the YFT2 allele suppressed expression of the downstream genes involved in the carotenoid biosynthesis pathway and carotenoids synthesis by a mechanism of the feed-forward regulation. In conclusion, we found that trans-splicing of YFT2 alters tomato fruit color, providing new insights into fruit color development.


Assuntos
Lycopersicon esculentum/metabolismo , Pigmentação/genética , Proteínas de Plantas/metabolismo , Processamento Alternativo , Carotenoides/metabolismo , Mapeamento Cromossômico , Clonagem Molecular , Cor , DNA Complementar/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Genes Recessivos , Teste de Complementação Genética , Genótipo , Lycopersicon esculentum/genética , Mutação , Proteínas de Plantas/genética , Trans-Splicing
14.
Mol Biol (Mosk) ; 53(3): 411-420, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184606

RESUMO

Antithrombin III (AT3) belongs to the superfamily of serine protease inhibitors (serpins) and is a major anticoagulant in physiological conditions. Based on SERPINC1 gene, a minigene coding for human AT3, which is valuable for medicine and biotechnology, was constructed by minimizing the size of lengthy introns and preserving the splicing site-flanking sequences. An analysis of the minigene splicing pattern identified one correct AT3 transcript and two alternatively spliced transcripts, which formed either due to minigene exons 2 and 3 skipping or an aberrant exon insertion via splicing at cryptic splicing sites in intron 1 of the minigene. Site-directed mutagenesis of the cryptic splicing sites successfully optimized the splicing pattern of the AT3 minigene to completely prevent the generation of the alternative transcripts. The presence of the cryptic splicing sites in intron 1 of the minigene was confirmed with Human Splicing Finder v. 3.1 software, thus demonstrating that putative alternative splicing sites are possible to identify in minimized or hybrid introns of minigenes and to eliminate via mutagenesis before experimentally testing the minigene splicing patterns. The approach to the design of minigenes together with the bioinformatical analysis of the nucleotide sequences of minigene introns can be used to construct minigenes in order to generate transgenic animals producing economically valuable proteins in the milk.


Assuntos
Processamento Alternativo/genética , Antitrombina III/genética , Sítios de Splice de RNA/genética , Éxons/genética , Humanos , Íntrons/genética
15.
BMC Bioinformatics ; 20(1): 231, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068132

RESUMO

BACKGROUND: In eukaryotes, most genes code for multiple transcript isoforms that are generated through the complex and tightly regulated process of RNA splicing. Despite arising from identical precursor transcripts, alternatively spliced RNAs can have dramatically different functions. Transcriptome complexity is elevated further by the production of circular RNAs (circRNAs), another class of mature RNA that results from the splicing of a downstream splice donor to an upstream splice acceptor. While there has been a rapid expansion of circRNA catalogs in the last few years through the utilization of next generation sequencing approaches, our understanding of the mechanisms and regulation of circular RNA biogenesis, the impact that circRNA generation has on parental transcript processing, and the functions carried out by circular RNAs remains limited. RESULTS: Here, we present a visualization and analysis tool, SpliceV, that rapidly plots all relevant forward- and back-splice data, with exon and single nucleotide level coverage information from RNA-seq experiments in a publication quality format. SpliceV also integrates analysis features that assist investigations into splicing regulation and transcript functions through the display of predicted RNA binding protein sites and the configuration of repetitive elements along the primary transcript. CONCLUSIONS: SpliceV is an easy-to-use splicing visualization tool, compatible with both Python 2.7 and 3+, and distributed under the GNU Public License. The source code is freely available for download at https://github.com/flemingtonlab/SpliceV and can be installed from PyPI using pip.


Assuntos
Processamento Alternativo/genética , Éxons/genética , Processamento de RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , RNA/genética
16.
Gene ; 706: 140-145, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31078657

RESUMO

BACKGROUND: Alternative splicing regulates most of protein-coding genes by producing diverse messenger RNA transcripts; and mis-splicing events can induce aberrant protein isoforms that contribute to cancer development. It is possible that genetic variations in splicing associated genes may regulate the formation of transcripts and multiple protein isoforms by affecting the splice regulatory elements. In this study, we aimed to determine whether genetic variations in the crucial alternative-splicing genes were associated with breast cancer risk. MATERIALS AND METHODS: A case-control study was conducted with 1064 breast cancer cases and 1073 healthy controls from China. A total of 16 tagging polymorphisms within three splicing factor-associated genes (SFRS3, ESRP1 and ESRP2) were genotyped by using Infinium BeadChip. The association between the polymorphisms and risk of breast cancer was evaluated by computing odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: The genotype distribution of rs2145048 in SFRS3 was different between cases and controls (Bonferroni corrected P = 0.022). After adjusting for age, age at menarche and menopausal status, the A allele of rs2145048 showed an inverse association with breast cancer risk in the additive model (adjusted OR = 0.81, 95% CI = 0.71-0.92, P = 0.001, Bonferroni corrected P = 0.016). In the stratification analysis, the association between rs2145048 A allele and breast cancer remained significant in subgroups of earlier menarche, older first born, premenopausal status, and ER/PR negative status. CONCLUSIONS: This study provided the first evidence that SFRS3 rs2145048 was associated with breast cancer susceptibility in Chinese women, which might represent a biomarker to improve the identification of individuals at high risk of this malignancy.


Assuntos
Neoplasias da Mama/genética , Fatores de Processamento de Serina-Arginina/genética , Adulto , Alelos , Processamento Alternativo/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia , Fatores de Risco , Fatores de Processamento de Serina-Arginina/fisiologia
17.
Nat Genet ; 51(5): 815-823, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043753

RESUMO

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10-9), CHMP4C at 8q21 (P = 2 × 10-11) and a PRC1 junction at 15q26 (P = 7 × 10-9). In vitro assays for CHMP4C showed that the associated variant induces allele-specific exon inclusion (P = 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the new genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to MYC. Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC.


Assuntos
Carcinoma Epitelial do Ovário/genética , Neoplasias Ovarianas/genética , Processamento Alternativo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Bases de Dados Genéticas , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Transcriptoma
18.
Gene ; 709: 17-24, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31102716

RESUMO

Angiopoietin-like protein 6, which is encoded by ANGPTL6 gene (also known as angiopoietin growth factor, AGF), has been extensively characterized with regard to its proposed functions as angiogenesis and energy metabolism. The present results showed the occurrence of alternative splicing by intron retention (IR) event in the bovine ANGPTL6 gene (bANGPTL6). By means of RT-PCR, TA clone and sequencing, we have shown that the bANGPTL6 gene has a splice variant generated by the retention of its partial intron 3. The computational analysis of the bANGPTL6 genomic sequence showed that its intron 3 has a high percentage of GC (62.31%) and a length of 199 nt, characteristics that have been associated with an IR event. The IR event does not interfere with the coding region as the bANGPTL6 prepropeptide is entirely coded in the third exon. Additionally, both the intronless (namely, bANGPTL6α) and intron-retaining (namely, bANGPTL6ß) ANGPTL6 transcripts are constitutively co-expressed in the bovine liver. Further, the relative expression level of different variants in liver was tested by both semi-RT-PCR and RT-qPCR methods. The results suggested bANGPTL6ß are significantly higher than bANGPTL6α. Overall, our findings will be helpful for studies on the molecular mechanism of IR events and the functions of ANGPTL6 gene. Specially, bANGPTL6ß gene probably contributes to a new target for treatment of obesity and obesity-related diseases.


Assuntos
Processamento Alternativo/genética , Proteínas Semelhantes a Angiopoietina/genética , Bovinos/genética , Íntrons/genética , Animais , Sequência de Bases , Clonagem Molecular , Feminino , Expressão Gênica , Fígado/metabolismo , Isoformas de Proteínas/genética
19.
Int J Mol Sci ; 20(9)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035721

RESUMO

Protein kinase Mζ is considered important for memory formation and maintenance in different species, including invertebrates. PKMζ participates in multiple molecular pathways in neurons, regulating translation initiation rate, AMPA receptors turnover, synaptic scaffolding assembly, and other processes. Here, for the first time, we established the sequence of mRNA encoding PKMζ homolog in land snail Helix lucorum. We annotated important features of this mRNA: domains, putative capping sites, translation starts, and splicing sites. We discovered that this mRNA has at least two isoforms, and one of them lacks sequence encoding C1 domain. C1 deletion may be unique for snail because it has not been previously found in other species. We performed behavioral experiments with snails, measured expression levels of identified isoforms, and confirmed that their expression correlates with one type of learning.


Assuntos
Aprendizagem , Proteína Quinase C/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Isoenzimas , Modelos Biológicos , Família Multigênica , Domínios e Motivos de Interação entre Proteínas , Proteína Quinase C/química , Proteína Quinase C/genética , Sítios de Splice de RNA , Relação Estrutura-Atividade , Transcrição Genética
20.
Adv Exp Med Biol ; 1132: 7-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037620

RESUMO

Although many studies have described the role of periostin in various diseases, the functions of periostin derived from alternative splicing and proteinase cleavage at its C-terminus remain unknown. Further experiments investigating the periostin structures that are relevant to diseases are essential for an in-depth understanding of their functions, which would accelerate their clinical applications by establishing new approaches for curing intractable diseases. Furthermore, this understanding would enhance our knowledge of novel functions of periostin related to stemness and response to mechanical stress .


Assuntos
Processamento Alternativo , Moléculas de Adesão Celular/genética , Humanos
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