scholarly journals Exploration of Alternative Splicing (AS) Events in MDV-Infected Chicken Spleens

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1857
Author(s):  
Lulu Wang ◽  
Gang Zheng ◽  
Yiming Yuan ◽  
Ziyi Wang ◽  
Changjun Liu ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Infection Process ◽  
Marek's Disease ◽  
Individual Development ◽  
Control Group ◽  
P Value ◽  
Marek’S Disease ◽  
Rna Seq ◽  
Infected Chicken ◽  
Structural Variations

Marek’s disease (MD) was an immunosuppression disease induced by Marek’s disease virus (MDV). MD caused huge economic loss to the global poultry industry, but it also provided an ideal model for studying diseases induced by the oncogenic virus. Alternative splicing (AS) simultaneously produced different isoform transcripts, which are involved in various diseases and individual development. To investigate AS events in MD, RNA-Seq was performed in tumorous spleens (TS), spleens from the survivors (SS) without any lesion after MDV infection, and non-infected chicken spleens (NS). In this study, 32,703 and 25,217 AS events were identified in TS and SS groups with NS group as the control group, and 1198, 1204, and 348 differently expressed (DE) AS events (p-value < 0.05 and FDR < 0.05) were identified in TS vs. NS, TS vs. SS, SS vs. NS, respectively. Additionally, Function enrichment analysis showed that ubiquitin-mediated proteolysis, p53 signaling pathway, and phosphatidylinositol signaling system were significantly enriched (p-value < 0.05). Small structural variations including SNP and indel were analyzed based on RNA-Seq data, and it showed that the TS group possessed more variants on the splice site region than those in SS and NS groups, which might cause more AS events in the TS group. Combined with previous circRNA data, we found that 287 genes could produce both circular and linear RNAs, which suggested these genes were more active in MD lymphoma transformation. This study has expanded the understanding of the MDV infection process and provided new insights for further analysis of resistance/susceptibility mechanisms.

scholarly journals Detection of p53 mutation and serum monitoring alert caused by Marek’s disease virus in poultry

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Huixia Zhang ◽  
Mengda Liu ◽  
Hui Zhang ◽  
Shengliang Cao ◽  
Yue Li ◽  
...  
Keyword(s):  
Human Cancer ◽  
Point Mutations ◽  
Suppressor Gene ◽  
Marek's Disease ◽  
Economic Losses ◽  
Control Group ◽  
Neoplastic Disease ◽  
Mutant P53 ◽  
Marek’S Disease ◽  
Infected Chicken

Abstract Background Marek’s disease (MD) is a chicken neoplastic disease, which brings huge economic losses to the global poultry industry. The wild type p53, a tumor suppressor gene, plays a key role in blocking cell cycle, promoting apoptosis, and maintaining the stability of the genome. However, the mutant p53 losses its tumor inhibitory role and become an oncogene when a mutation has happened. Results The mutation rate of p53 was 60% in the experimentally and naturally infected chickens. The mutations included point-mutations and deletions, and mostly located in the DNA-binding domain. The mutated p53 was expressed in various tumor tissues in an infected chicken. The mutant P53 proteins were notably accumulated in the cytoplasm due to the loss in the function of nuclear localization. Unlike the study on human cancer, the concentrations of P53 in the serums of MD infected chicken were significantly lower than the control group. Conclusions The p53 mutations were apparent in the development of MD. P53 and P53 antibody level in serum could be a useful marker in the diagnosis and surveillance of MD.

scholarly journals Detection of p53 mutation and serum monitoring alert caused by Marek's disease virus

2020 ◽  
Author(s):  
Huixia Zhang ◽  
Mengda Liu ◽  
Hui Zhang ◽  
Shengliang Cao ◽  
Yue Li ◽  
...  
Keyword(s):  
Human Cancer ◽  
Point Mutations ◽  
Suppressor Gene ◽  
P53 Mutation ◽  
Marek's Disease ◽  
Economic Losses ◽  
Control Group ◽  
Neoplastic Disease ◽  
Marek’S Disease ◽  
Infected Chicken

Abstract Background: Marek’s disease as a chicken neoplastic disease, brings huge economic losses to the global poultry industry. The tumor suppressor gene, wild type P53, plays a key role in blocking cell cycle, promoting apoptosis and maintaining stability of genome. However, the p53 could become an oncogene from a tumor inhibitory role, if a mutation happened. Results: The mutation rate of p53 was 60 percent in experimentally and naturally infected chickens. The mutations included point-mutations and deletions, and mostly located in the DNA-binding domain. The mutated P53 can be expressed in tumors of various tissues in an infected chicken. They accumulated in cytoplasm due to the loss of nuclear localization function. Unlike the researches on human cancer, the concentration of P53 serum of MD infected chicken was significantly lower than control group. Conclusions: The p53 mutations were relevant with the development of MD. Detecting the concertation of P53 and P53 antibody in serum could be helpful for diagnosis and monitor of MD.

scholarly journals Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation

Immuno ◽  
2021 ◽  
Vol 1 (4) ◽  
pp. 499-517
Author(s):  
Bruce R. Southey ◽  
Marissa R. Keever-Keigher ◽  
Haley E. Rymut ◽  
Laurie A. Rund ◽  
Rodney W. Johnson ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Immune Activation ◽  
Fatty Liver Disease ◽  
P Value ◽  
Rna Seq ◽  
Alcoholic Fatty Liver ◽  
Maternal Immune Activation ◽  
Precise Understanding ◽  
Splicing Patterns ◽  
Alcoholic Fatty Liver Disease

The inflammatory response of gestating females to infection or stress can disrupt gene expression in the offspring’s amygdala, resulting in lasting neurodevelopmental, physiological, and behavioral disorders. The effects of maternal immune activation (MIA) can be impacted by the offspring’s sex and exposure to additional stressors later in life. The objectives of this study were to investigate the disruption of alternative splicing patterns associated with MIA in the offspring’s amygdala and characterize this disruption in the context of the second stress of weaning and sex. Differential alternative splicing was tested on the RNA-seq profiles of a pig model of viral-induced MIA. Compared to controls, MIA was associated with the differential alternative splicing (FDR-adjusted p-value < 0.1) of 292 and 240 genes in weaned females and males, respectively, whereas 132 and 176 genes were differentially spliced in control nursed female and male, respectively. The majority of the differentially spliced (FDR-adjusted p-value < 0.001) genes (e.g., SHANK1, ZNF672, KCNA6) and many associated enriched pathways (e.g., Fc gamma R-mediated phagocytosis, non-alcoholic fatty liver disease, and cGMP-PKG signaling) have been reported in MIA-related disorders including autism and schizophrenia in humans. Differential alternative splicing associated with MIA was detected in the gene MAG across all sex-stress groups except for unstressed males and SLC2A11 across all groups except unstressed females. Precise understanding of the effect of MIA across second stressors and sexes necessitates the consideration of splicing isoform profiles.

scholarly journals Detection of p53 mutation and serum monitoring alert caused by Marek's disease virus

2020 ◽  
Author(s):  
Huixia Zhang ◽  
Mengda Liu ◽  
Hui Zhang ◽  
Shengliang Cao ◽  
Yue Li ◽  
...  
Keyword(s):  
Point Mutation ◽  
Suppressor Gene ◽  
P53 Mutation ◽  
Marek's Disease ◽  
Economic Losses ◽  
Neoplastic Disease ◽  
Marek’S Disease ◽  
Infected Chicken ◽  
Serum Monitoring ◽  
Risk Of Cancer

Abstract Background Marek’s disease (MD), as a chicken neoplastic disease, brings huge economic losses to the global poultry industry. The tumor suppressor gene, wild type P53 plays a key role in blocking cell cycle, promoting apoptosis and maintaining stability of genome. The p53 function could change to that of an oncogene from a tumor inhibitory role, if a mutation happened. It will increase risk of cancer incidence. Results It was found that the mutation rate of p53 was 60 percent in experimentally infected and naturally infected chickens. The mutations included point-mutation and deletions, and mostly located in the DNA-binding domain. The most common point mutation happened in five sites, which were 651, 786, 828, 864 and 879 respectively. The mutated P53 can be expressed in tumors of various tissues in an infected chicken because of the lengthening of the half-life of mutated P53. Due to the loss of nuclear localization function, most of mutated P53 were expressed in cytoplasm. The concentration of P53 was decrease in serum of MD infected chicken. Conclusions Results of the current study suggested that p53 mutations with different types were common in MD, and most of mutated P53 were expressed in cytoplasm. Detecting the concertation of P53 and P53 antibody in serum could be helpful for diagnosis and monitor of MD.

scholarly journals Alternative Splicing Is a Frequent Event and Impacts Clinical Outcome in Myeloma: A Large RNA-Seq Data Analysis of Newly-Diagnosed Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 638-638 ◽  
Author(s):  
Naim Rashid ◽  
Stephane Minvielle ◽  
Florence Magrangeas ◽  
Mehmet Kemal Samur ◽  
Alice Clynen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Exon Skipping ◽  
P Value ◽  
Newly Diagnosed ◽  
Rna Seq ◽  
Exon Level ◽  
Total Gene Expression ◽  
Isoform Switching ◽  
Alternative Splicing Events

Abstract Alternative splicing is an important post-translational change that alters gene function. Misregulation of alternative splicing has been implicated in number of disease processes including cancer. Here we have analyzed alternative splicing in myeloma using high throughput RNA-seq. Our analytic pipeline for RNA-seq data used in this investigation not only provides information on expression levels for genes, but also provides information on the expression of known splice variants of genes (isoforms), and can identify novel exon level events across individuals (i.e. exon skipping events). We conducted a study of 328 newly-diagnosed patients with multiple myeloma treated homogeneously with novel agent combination containting lenalidomide, bortezomib and dexamethsone with or without high-dose melphalan followed by lenalidomide maintenance in the IFM/DFCI study. RNA isolated from purified CD138+ MM cells collected at the time of diagnosis and from 18 normal donor plasma cells were processed by RNA-seq (100 million paired end reads on Illumina HiSeq) and analyzed using a custom computational and statistical pipeline. Following read alignment to hg19, we utilized RSEM to quantify both gene-level and isoform-level expression of known ENSEMBL transcripts. We then implemented a novel testing approach based on compositional regression to discover genes that show significant isoform switching between the 328 MM samples and 18 Normal Plasma Cell (NPC) samples from healthy donors. Using various programs and their modifications, we also identified novel alternative splicing events, such as exon skipping and mutually exclusive exon usage, among others. Patient data for MM characteristics, cytogenetic and FISH as well as clinical survival outcomes were also analyzed and correlated with genomic data. We observed over 600 genes showing significant changes in relative isoform abundances (isoform switching) between MM and normal samples. A number of previously characterized genes including MYCL1 (adj. p = 0.0014) and CCND3 (adj. p = 0.0013), and MAP kinase-related genes (MAP3K8, MAPKAPK2, MAPKAPK3, MAP4K4) exhibited significant isoform switching compared to normal, in addition to some not well characterized genes. Genes showing the greatest magnitude of isoform switching include MEFV (adj. p = 2.7 x 10-5), showing a two fold change in the relative major isoform abundance compared to normal, and has been previously shown to have a role in lymphoid neoplasms. We applied hierarchical clustering to the isoforms showing significant changes in isoform-switching and identified 4 distinct clusters, which are currently being investigated for correlation with clinical subtypes of MM. Exon level analyses of alternative splicing events, such as exon skipping, are currently underway. Clinical data including MM characteristics, cytogenetics, FISH and survival outcomes was available for a subset of 265 patients. We found that 109 genes showed significant isoform switching between t(4;14) and non-t(4;14) patients, such as CD44 (adj. p =1.8 x 10-6) and WHSC1 (adj. p =5.1 x 10-28). Comparing del17p (28 in total) and non del17p patients, we found no significant splicing changes after multiple testing adjustment. Of these genes, only a subset (40%) were shown to be differentially expressed in terms of total gene expression, suggesting the importance of examining alternative splicing events in addition to total gene expression. With respect to treatment response, we compared the expression of gene isoforms between patients achieving complete response (CR) versus others and identified 38 isoforms associated with response to treatment (adj. p value < 0.05), with SEPT9, SLC2A5, and UBX6 having the strongest associations (adj. p-value < 3 x 10-4). Using a univariate cox regression model, 4 spliced isoforms relating to 3 genes were identified as having significant correlation with event-free survival (EFS) (FDR-adjusted cox p value < 0.05). We are in the process of now integrating the gene expression data with altered splicing data to develop an integrated survival model. In summary, this study highlights the significant frequency, biological and clinical importance of alternative splicing in MM and points to the need for evaluation of not only the expression level of genes but also post-translational modifications. The genes identified here are important targets for therapy as well as possible immune modulation. Disclosures Moreau: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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