Dataset Information

Alternative splicing of the trout Pax5 gene and identification of novel B cell populations using Pax5 signatures.

ABSTRACT: Pax5 is an alternatively spliced transcription factor that regulates B cell development and activation. The function of specific Pax5 isoforms is unknown. Here we report the existence of seven alternatively spliced isoforms of Pax5 in the rainbow trout. We hypothesized that B cells differentially express specific Pax5 isoforms as a means of modulating Pax5 activity during cell maturation. Flow cytometric analyses using Pax5-specific antibodies recognizing the paired domain, a central (exon 6-encoding) domain, or the C-terminus, revealed the existence of distinct Pax5-expressing cell populations in trout immune tissues. Additionally, using the transcription factor EBF, we show that Pax5 isoforms lacking a paired domain are already expressed at the earliest stages of trout (B) lymphopoiesis, and unexpectedly, that minor populations of such cells reside in blood and spleen. These data support use of differentially expressed Pax5 isoforms to identify novel B cell subsets in the form of Pax5 tissue signatures, and as such, provides new biomarkers for malignancy, infectious disease, and disease resistance in trout and humans.

SUBMITTER: MacMurray E

PROVIDER: S-EPMC3932526 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Alternative splicing of the trout Pax5 gene and identification of novel B cell populations using Pax5 signatures.

MacMurray Elizabeth E Barr Maggie M Bruce Amber A Epp Lidia L Zwollo Patty P

Developmental and comparative immunology 20130621 2

Pax5 is an alternatively spliced transcription factor that regulates B cell development and activation. The function of specific Pax5 isoforms is unknown. Here we report the existence of seven alternatively spliced isoforms of Pax5 in the rainbow trout. We hypothesized that B cells differentially express specific Pax5 isoforms as a means of modulating Pax5 activity during cell maturation. Flow cytometric analyses using Pax5-specific antibodies recognizing the paired domain, a central (exon 6-enc ...[more]

PMID: 23796789

Similar Datasets

Project description:BackgroundIndividual immune-related alternative splicing (AS) events have been found to be significant in immune regulation and cancer prognosis. However, a comprehensive analysis of AS events in cancer cells based on immune-related genes (IRGs) has not been performed, and its clinical value is unknown.MethodsColon cancer cases with AS data were obtained from TCGA, and then, we identified overall survival-related AS events (OS-ASEs) based on IRGs by univariate analyses. Using Lasso regression, multivariate Cox regression, Kaplan-Meier analysis and nomograms, we constructed an AS risk model based on the calculated risk score. Furthermore, associations of the risk score with clinical and immune features were confirmed through the Wilcoxon rank sum test, association analysis, etc. Finally, by qRT-PCR, cell coculture and CCK-8 analyses, we validated the significance of OS-ASEs in colon cancer cell lines and clinical samples.ResultsA total of 3,119 immune-related AS events and 183 OS-ASEs were identified, and 9 OS-ASEs were ultimately used to construct a comprehensive risk model for colon cancer patients. Low-risk patients had better OS and DFS rates than high risk patients. Furthermore, a high risk score corresponded to high numbers of multiple tumour-infiltrating immune cells and high expression of HLA-D region genes and immune checkpoint genes. Notably, we identified for the first time that anti-PD-L1 or anti-CTLA-4 antibodies may decrease the OS of specific colon cancer patients in the low-risk group. Additionally, the in vitro experiment validated that CD46-9652-ES and PSMC5-43011-ES are positively correlated with the infiltration of immune cells and promote the growth of colon cancer cells. CD46-9652-ES can contribute to T cell-mediated tumour cell killing. PSMC5-43011-ES was observed to induce M2 polarization of macrophages.ConclusionsThis study identified and validated immune-related prognostic AS signatures that can be used as a novel AS prognostic model and provide a novel understanding of the relationship between the immune microenvironment and clinical outcomes.

Project description:Purpose: Alternative splicing (AS) is a post-transcriptional process that plays a significant role in enhancing the diversity of transcription and protein. Accumulating evidences have demonstrated that dysregulation of AS is associated with oncogenic processes. However, AS signature specifically in lung squamous cell carcinoma (LUSC) remains unknown. This study aimed to evaluate the prognostic values of AS events in LUSC patients. Methods: The RNA-seq data, AS events data and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis was performed to identify survival-related AS events and survival-related parent genes were subjected to Gene Ontology enrichment analysis and gene network analysis. The least absolute shrinkage and selection operator (LASSO) method and multivariate Cox regression analysis were used to construct prognostic prediction models, and their predictive values were assessed by Kaplan-Meier analysis and receiver operating characteristic (ROC) curves. Then a nomogram was established to predict the survival of LUSC patients. And the interaction network of splicing factors (SFs) and survival-related AS events was constructed by Spearman correlation analysis and visualized by Cytoscape. Results: Totally, 467 LUSC patients were included in this study and 1,991 survival-related AS events within 1,433 genes were identified. SMAD4, FOS, POLR2L, and RNPS1 were the hub genes in the gene interaction network. Eight prognostic prediction models (seven types of AS and all AS) were constructed and all exhibited high efficiency in distinguishing good or poor survival of LUSC patients. The final integrated prediction model including all types of AS events exhibited the best prognostic power with the maximum AUC values of 0.778, 0.816, 0.814 in 1, 3, 5 years ROC curves, respectively. Meanwhile, the nomogram performed well in predicting the 1-, 3-, and 5-year survival of LUSC patients. In addition, the SF-AS regulatory network uncovered a significant correlation between SFs and survival-related AS events. Conclusion: This is the first comprehensive study to analyze the role of AS events in LUSC specifically, which improves our understanding of the prognostic value of survival-related AS events for LUSC. And these survival-related AS events might serve as novel prognostic biomarkers and drug therapeutic targets for LUSC.

Project description:Background: Kidney renal clear cell carcinoma (KIRC) is the malignancy originated from the renal epithelium, with a high rate of distant metastasis. Aberrant alternative splicing (AS) of pre-mRNA are widely reported to be involved in the tumorigenesis and metastasis of multiple cancers. The aim of this study is to explore the mechanism of alternative splicing events (ASEs) underlying tumorigenesis and metastasis of KIRC. Methods: RNA-seq of 537 KIRC samples downloaded from the TCGA database and ASEs data from the TCGASpliceSeq database were used to identify ASEs in patients with KIRC. The univariate and Lasso regression analysis were used to screen the most significant overall survival-related ASEs (OS-SEs). Based on those, the OS-SEs model was proposed. The interaction network of OS-SEs and splicing factors (SFs) with absolute value of correlation coefficient value >0.750 was constructed by Pearson correlation analysis. The OS-SEs significantly related to distant metastasis and clinical stage were identified by non-parametric test, and those were also integrated into co-expression analysis with prognosis-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways identified by Gene Set Variation Analysis (GSVA). ASEs with significance were selected for multiple online database validation. Results: A total of prognostic 6,081 overall survival-related ASEs (OS-SEs) were identified by univariate Cox regression analysis and a prediction model was constructed based on 5 OS-SEs screened by Lasso regression with the Area Under Curve of 0.788. Its risk score was also illustrated to be an independent predictor, which the good reliability of the model. Among 390 identified candidate SFs, DExD-Box Helicase 39B (DDX39B) was significantly correlated with OS and metastasis. After external database validation, Retained Intron of Ras Homolog Family Member T2 (RHOT2) and T-Cell Immune Regulator 1 (TCIRG1) were identified. In the co-expression analysis, overlapped co-expression signal pathways for RHOT2 and TCIRG1 were sphingolipid metabolism and N-glycan biosynthesis. Conclusions: Based on the results of comprehensive bioinformatic analysis, we proposed that aberrant DDX39B regulated RHOT2-32938-RI and TCIRG1-17288-RI might be associated with the tumorigenesis, metastasis, and poor prognosis of KIRC via sphingolipid metabolism or N-glycan biosynthesis pathway.

Dataset Information

Alternative splicing of the trout Pax5 gene and identification of novel B cell populations using Pax5 signatures.

Publications

Alternative splicing of the trout Pax5 gene and identification of novel B cell populations using Pax5 signatures.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets