PCBP-1 regulates the transcription and alternative splicing of inflammation and ubiquitination-related genes in Parkinson’s disease model
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE196153 | GEO | 2022/07/13
REPOSITORIES: GEO
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Project description:CELF6 (CUGBP Elav-Like Family Member 6), a typical RNA binding protein, can regulate alternative splicing of pre-mRNAs, and may also participate in mRNA editing and translation. As a tumor suppressor, CELF6 is abnormally low expressed in colon cancer, breast cancer and other tumors, and is closely related to proliferation, invasion, and migration. Recent studies have shown that CELF6 has abnormally low expression in lung cancer tissues, and is increased after ultra-hypoxia treatment in A549 cells, however, the functions and molecular mechanisms of CELF6 in lung cancer are still unclear. We overexpressed CELF6 in human non-small cell lung cancer cells (A549), and set up a control; after collecting cells, we used RNA sequencing to screen for genes with significant differential expression (DEGs) after CELF6 overexpression, and significantly alternative splicing events (ASEs). CELF6 overexpression widely regulates the expression of related genes in immune response，Inflammation response, Innate immune response，TNF signaling pathway, cell adhesion molecules (CAMs) and so on. We found that CELF6 can inhibit the expression many immune-related genes, such as TNFSF10、CCL5、JUNB、BIRC3、MLKL、PIK3R2、CCL20、STAT1、MYD88 and CFS1，which mainly function in promoting tumorigenesis in lung cancer. These DEGs were validated by reverse transcriptase quantitative polymerase chain reaction (RT-PCR). In addition, CELF6 regulates the alternative splicing of a large number of genes which were enriched in p53 signaling pathway and apoptosis，such as TP53 and CD44. This study is the first to analyze the transcriptome analysis of differential gene expression and alternative splicing of CELF6 overexpression. which will provide a new idea for the gene regulation mechanism mediated by CELF6 in the production and development of NSCLC.
2022-07-11 | GSE185865 | GEO
Project description:Farnesyl diphosphate synthase (FDPS), an essencial enzyme involved in mevalonate pathway, is implicated in cancers and osteoporosis by catalyzing head to tail condensation of two molecules of isopentenyl pyrophosphate with dimethylallyl pyrophosphate to form farnesyl pyrophosphate. It has also been identified as an RNA-binding protein (RBP). However, it’s exactly RNA-binding function in diseases, up to now, remain unknown. In the present study, the function of FDPS in HeLa cells was investigated with FDPS overexpression. The results showed that FDPS overexpression promoted proliferation in HeLa cells. FDPS overexpression extensively regulated the expression of genes in cell proliferation, cytokine-mediated signaling pathway, and extracellular matrix organization. In addition, FDPS extensively regulated the alternative splicing of numbers of genes related with osteoporosis, including NAB1, FGFR3, and ALPL, and FDPS-regulated DEGs and ASEs were highly validated by RT-qPCR. This is the first study to investigate the properties of FDPS as an RBP from a genome-wide perspective, our results suggested that FDPS acts as an RBP playing an important role in cancer progression and osteoporosis by altering gene expression and regulating alternative splicing, which contributes to a precise understanding of potentially FDPS-targeted therapies.
2023-02-06 | GSE151605 | GEO
Project description:Except for a few genes known to have oncogenic spliceforms in gastric cancer, the full scope of aberrant splicing in gastric oncogenesis remains unclear. In this study, we elucidated the alternative splicing events associated with gastric carcinogenesis and identified upstream regulators governing these events. We performed RNA-seq on 19 matched tumor/normal pairs and a panel of gastric cancer cell lines, and identified 361 tumor associated (TA) alternative splicing events (ASEs), which included known oncogenic ASEs in genes such as INSR, FGFR2, CD44 and KRAS. We further identified 8 splicing factors dysregulated in gastric tumors, the expression of which are correlated to the splice ratio of the TA ASEs. We thereby constructed a dysregulated splicing network in gastric cancer, consisting of alternative splicing changes correlated to their potential regulators. This network featured three potential regulatory modules centered around the splicing factors ESRP2, MBNL1 and PTPB1. Knockdown of each splicing factor led to the expected changes in splicing of approximately half of the ASEs assayed. Thus, dysregulation of the splicing factors indeed was the cause of many of the TA ASEs. Pathway enrichment analysis showed that genes affected by tumor associated splicing were pre-dominantly involved in cytoskeletal organization. Concordant with this, knockdown of the splicing factors regulating the TA ASEs led to the expected changes in trans-well migration activity. Thus, we have established for the first time a comprehensive splicing network that likely drives gastric tumor progression, based on which novel therapeutic targets can be identified for further evaluation.
| EGAS00001002256 | EGA
Project description:The epithelial splicing regulatory proteins 1 and 2 (ESRP1/2) control the epithelial‐to‐mesenchymal transition (EMT) splicing program in cancer. However, their exact role in Breast Cancer (BC) remains under debate. Here, we report that ESRP1, but not ESRP2, is overexpressed in luminal BCs patients with poor prognosis and correlates with Estrogen Receptor α (ERα) mRNA levels. Analysis of ERα genome binding profiles in both cell lines and primary breast tumors showed its binding on both ESRP1 and ESRP2 promoters, and the expression of these genes strongly decreased by ERα silencing in hormone-deprived conditions (apoERα). The combined knock down of ESRP1/2 in MCF-7 cells followed by RNA-Seq, revealed the dysregulation of 754 genes expression, with a widespread alteration of alternative splicing events (ASEs) of genes involved in cell signaling, metabolism, cell growth, and EMT. Functional network analysis of ASEs that correlate with ESRP1/2 expression in ERα+ BCs showed RAC1 as the hub node in the protein-protein interactions altered by ESRP1/2 silencing. The comparison of apoERα- and ESRP-modulated ASEs revealed 63 commonly regulated events, including 27 detected both in primary BCs and endocrine resistant cell lines. Our data support a functional implication of the ERα-ESRP1/2 axis in the onset and progression of BC by controlling the splicing patterns of related genes.
2022-06-20 | GSE206474 | GEO
Project description:Background: Acacetin is a natural flavonoid known for its anti-tumor, antioxidant, and anti-inflammatory properties. Our previous studies have shown its protective effects against cerebral ischemia-reperfusion injury (IRI), but the underlying molecular mechanisms remain unclear. Purpose: The study delves into acacetin's mechanism in mitigating cerebral IRI, with a focus on transcriptomic insights. Methods: We established the oxygen-glucose deprivation/re-oxygenation (OGD/R) model in BV2 microglia, treating them with 10μM acacetin. Then we assessed cell proliferation using CCK-8 and measured Lactate Dehydrogenase (LDH) release. High-throughput RNA sequencing (RNA-seq) underpinned the analysis of differentially expressed genes (DEGs) and long non-coding RNAs (lncRNAs), functional enrichment, and alternative splicing events (ASEs), validated by reverse transcription–quantitative polymerase chain reaction (RT-qPCR). Results: OGD/R injury significantly impaired cell proliferation and increased LDH release, effects mitigated by acacetin. RNA-seq identified 2,148 upregulated and 2,135 downregulated DEGs post-OGD/R. In contrast, the acacetin-treated group showed 248 upregulated and 240 downregulated DEGs compared to the OGD/R group. All DEGs were enriched in both Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Overlapping analysis indicated that acacetin treatment reversed the expression of 203 genes affected by OGD/R, including inflammation-related genes such as Isg15, Fcgr1, Il1b, and Parp12. Moreover, the oxidative stress-related gene, Mt2, was downregulated post-OGD/R but upregulated following acacetin treatment. We further found that OGD/R and acacetin treatment could modulate gene splicing events, impacting cell apoptosis or inflammatory responses, such as the A3SS splicing event in the Trim47 gene. RNA-seq also highlighted differential expression of numerous lncRNAs, particularly the upregulation of lncRNA Rmrp and Terc post-OGD/R and their subsequent downregulation post-acacetin treatment. These lncRNAs might regulate cell proliferation through mediating target gene expressions. RT-qPCR validation confirmed these findings. Conclusion: Significant upregulation of genes and ASEs linked to oxidative stress and inflammatory response is observed in cerebral IRI. Acacetin intervention reverses these effects, highlighting its mechanism in alleviating the injury by modulating gene expression and splicing events.
2024-05-31 | GSE249957 | GEO
Project description:Although the function of DNA methylation in gene promoter regions is well established in transcriptional repression, the function of the evolutionarily conserved widespread distribution of DNA methylation in gene body regions remains incompletely understood. Here, we show that DNA methylation is enriched in included alternatively spliced exons (ASEs) and inhibiting DNA methylation results in aberrant splicing of ASEs. The methyl-CpG binding protein MeCP2 is enriched in included ASEs, particularly those that are also highly DNA methylated, and inhibition of DNA methylation disrupts specific targeting of MeCP2 to exons. Interestingly, ablation of MeCP2 results in increased nucleosome acetylation and aberrant skipping events of ASEs. We further show that inhibition of histone deacetylases leads to a highly significant overlap of exon skipping events caused by knocking-down MeCP2. Together, our data indicate that intragenic DNA methylation operates in exon definition to modulate alternative splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through its established interaction with HDACs. MeCP2 ChIP-Seq in IMR90 and HCT116 cells
2013-08-13 | E-GEOD-47677 | biostudies-arrayexpress
Project description:Although the function of DNA methylation in gene promoter regions is well established in transcriptional repression, the function of the evolutionarily conserved widespread distribution of DNA methylation in gene body regions remains incompletely understood. Here, we show that DNA methylation is enriched in included alternatively spliced exons (ASEs) and inhibiting DNA methylation results in aberrant splicing of ASEs. The methyl-CpG binding protein MeCP2 is enriched in included ASEs, particularly those that are also highly DNA methylated, and inhibition of DNA methylation disrupts specific targeting of MeCP2 to exons. Interestingly, ablation of MeCP2 results in increased nucleosome acetylation and aberrant skipping events of ASEs. We further show that inhibition of histone deacetylases leads to a highly significant overlap of exon skipping events caused by knocking-down MeCP2. Together, our data indicate that intragenic DNA methylation operates in exon definition to modulate alternative splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through its established interaction with HDACs. RNA-Seq in IMR90 and HCT116
2013-08-13 | E-GEOD-47488 | biostudies-arrayexpress
Project description:Mitochondrial transcription factor A (TFAM) is associated with a number of neurodegenerative diseases and also with asthma. TFAM deficiency-induced mitochondrial DNA stress primes the antiviral innate immune response in mouse embryonic fibroblasts. In this study, we overexpressed TFAM in human lung epithelial cells (A549), then obtained and analyzed the TFAM-regulated transcriptome by Illumina-sequencing technology. We found that TFAM overexpression down-regulated and up-regulated the expression 642 and 169 genes (DEGs), respectively. The TFAM-repressed genes were highly enriched in cytokine-mediated signaling pathway, type I interferon- and INFmediated signaling pathways, and viral response pathways. We also revealed that 2563 alternative splicing events in 1796 genes (ASG) were de-regulated upon TFAM overexpression. These TFAM-responding ASGs were strongly enriched in DNA repair, nerve growth factor receptor signaling pathway, and also transcription regulation. Further analysis revealed that the promoters of TFAM-repressed DEGs were enriched by DNA binding motifs of transcription factors whose alternative splicing regulated by TFAM. These findings suggested that TFAM regulates not only immune response gene expression in human lung epithelial cells, but also alternative splicing which may play a role in mediating transcriptional regulation. This TFAM-centered gene regulation network could be targeted in developing therapies against various diseases.
2021-12-15 | GSE162384 | GEO
Project description:RNA-binding proteins (RBPs) have important roles in orchestrating posttranscriptional regulation and modulating many tumorigenesis events. SERBP1 has been recognized as an important regulator in multiple cancers, while it remains unclear whether SERBP1-regulated gene expression at the transcriptome-wide level is significantly correlated with tumorigenesis.We overexpressed SERBP1 in HeLa cells and explored whether SERBP1 overexpression (SERBP1-OE) affects the proliferation and apoptosis of HeLa cells. We analyzed the transcriptome-wide gene expression changes and alternative splicing changes mediated by SERBP1-OE using transcriptome sequencing method (RNA-seq). RT-qPCR was conducted to assay SERBP1-regulated alternative splicing.SERBP1-OE induced the apoptosis of HeLa cells. The downregulated genes were strongly enriched in the cell proliferation and apoptosis pathways according to the GO analysis, including FOS, FOSB, PAK6 and RAB26. The genes undergoing at least one SERBP1-regulated alternative splicing event were enriched in transcriptional regulation, suggesting a mechanism of the regulation of gene expression, and in pyruvate and fatty acid metabolic processes critical for tumorigenesis events. The SERBP1-regulated alternative splicing of ME3, LPIN3, CROT，PDP1, SLC27A1 and ALKBH7 was validated by RT-qPCR analysis.We for the first time demonstrated the cellular function and molecular targets of SERBP1 in HeLa cells at transcriptional and post-transcriptional levels. The SERBP1-regulated gene expression and alternative splicing networks revealed by this study provide important information for exploring the functional roles and regulatory mechanisms of SERBP1 in cancer development and progression.
2022-09-02 | GSE192950 | GEO
Project description:Eukaryotic proteome diversity exceeds that encoded within individual genes, and results in part from alternative splicing events of pre-messenger RNA. The diversity of these splicing events can shape the outcome in development and differentiation of normal tissues, and is important in pathogenic circumstances such as cancer and some heritable conditions. A role for alternative splicing of eukaryotic genes in response to viral and intracellular bacterial infections has only recently been recognized, and plays an important role in providing fitness for microbial survival, while potentially enhancing pathogenicity. Anaplasma phagocytophilum survives within mammalian neutrophils by reshaping transcriptional programs that govern cellular functions. We applied next generation RNAseq to ATRA-differentiated HL-60 cells established to possess transcriptional and functional responses similar to A. phagocytophilum-infected human neutrophils. This demonstrated an increase in transcripts with infection and high proportion of alternatively spliced transcript events (ASEs) for which predicted gene ontology processes were in part distinct from those identified by evaluation of single transcripts or gene-level analyses alone. The alternative isoforms are not on average shorter, and no alternative splicing in genes encoding spliceosome components is noted. Although not evident at gene-level analyses, individual spliceosome transcripts that impact nearly all spliceosome components were significantly upregulated. How the distinct GO processes predicted by ASEs are regulated by infection and whether they are relevant to fitness or pathogenicity of A. phagocytophilum should be addressed in more detailed studies.
2018-02-13 | GSE107770 | GEO