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Filamin B extensively regulates the transcription and alternative splicing and is associated with apoptosis in HeLa cells

ABSTRACT: Post-transcriptional mechanisms is an important means for the body to fight against cancer, and it may also be hijacked by tumor cells to help them adapt to local microenvironment. Filamin B (FLNB), an actin-binding protein and providing crucial scaffolds for cell motility and signaling, was also identified as one of RNA binding proteins (RBPs). Recent works showed that FLNB might play important role not only in skeletal development but also in the regulation of tumorigenesis. However, the effects of dysregulated expression of FLNB at a molecular level are unclear. In this study, we used RNA-seq to analyze the global transcriptional level changes and alternative splicing between the knocked-down FLNB and the control in Hela cells. Reduced levels of FLNB led to a significant decrease in cell apoptosis, compared with control cells. FLNB knockdown extensively regulated the expression of genes in cell apoptosis, tumorigenesis, metastases, transmembrane transport, cartilage and nerve development. Moreover, FLNB regulated alternative splicing of a large number of genes enriched in cell death and apoptotic process. Meanwhile, some genes and alternative splicing related to skeletal development were enriched and regulated by FLNB. Quantitative RT-PCR confirmed the FLNB-regulated transcription and alternative splicing. This study provides the first transcriptome-wide analysis of FLNB. Our findings indicated that FLNB may play an important regulatory role in cancer cell apoptosis via the regulation of alternative splicing and potentially transcription, which greatly expands the current understanding of the mechanisms of FLNB mediated gene regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134769 | GEO | 2020/05/19

REPOSITORIES: GEO

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Filamin B extensively regulates the transcription and alternative splicing and is associated with apoptosis in HeLa cells

Project description:Filamin B extensively regulates the transcription and alternative splicing and is associated with apoptosis in HeLa cells

| PRJNA556368 | ENA

SERBP1 affects the apoptotic level by regulating the expression and alternative splicing of cellular and metabolic process genes in HeLa cells

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

eCLIP in immortalized human mammary epithelial cells

Project description:The epithelial-to-mesenchymal transition (EMT) contributes to tumor heterogeneity and has been implicated in tumor initiation and metastasis. To systematically identify genes involved in EMT, we performed a genome-scale expression screen in human mammary epithelial cells and found a striking enrichment in RNA splicing factors. In particular, the RNA-binding proteins QKI and RBFOX1 were necessary and sufficient to promote EMT and stem-like states. Among the transcripts cooperatively regulated by both factors, we found that alternative splicing of the actin-binding protein FLNB plays an essential role in the regulation of EMT. The skipping of FLNB exon 30 and the elevated expression of QKI were strongly associated with EMT gene signatures in both basal B subtype breast cancer cell lines and basal-like breast cancer patient samples. These observations demonstrate that alternative splicing regulated by QKI and RBFOX1 plays an active role in promoting EMT in basal-like breast cancers.

2018-04-25 | GSE98209 | GEO

RNA-sequencing in immortalized human mammary epithelial cells

2018-04-25 | GSE98208 | GEO

The Refilin/Filamin complex regulates filipodia dynamics in oligodendrocyte progenitor cells.

Project description:Actin assembly and dynamics control the shape, motility and functions of diverse cell types. Programme for controlling theses dynamics is hard-coded into actin binding proteins and regulatory proteins. Refilins (RefilinA and RefilinB) are short lived regulatory proteins that interact with the actin-binding protein Filamin to convert it from an actin branching protein into one that bundles. We here show that different mechanisms converge to increase Refilin level in brain NG2+ precursor cells (polydendrocytes) committed to differentiate into the oligodendrocyte lineage. RefilinA is up-regulated through transcriptional activation during commitment into oligodendrocyte progenitor cells (OPC). RefilinB expression relies on PDGF signalling and is further stabilized by a unique auto-inhibitory domain masking the adjacent conserved PEST degradation signal. In NG2+ precursor cells and OPC, the RefilinB/Filamin complex localizes on filipodia protrusions and filipodial processes. Stable ectopic expression of Refilins in cells stimulates membrane remodelling dynamics linked with filipodia growth. These studies extend the function of the Refilin/FLNA complex to cell membrane remodelling linked with reorganization of underlying actin cytoskeleton. We performed whole transcriptomic analysis on the three cell population derived from OPC cells. Three different cultures were done and for each experiment we compared each cell population (NG2+, NG2+/A2B5 and O4) to the other 2 cell populations.

2013-05-01 | E-GEOD-37600 | biostudies-arrayexpress

The Refilin/Filamin complex regulates filipodia dynamics in oligodendrocyte progenitor cells.

2013-05-01 | GSE37600 | GEO

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Project description:Filamin C is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familiar and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from filamin C and abolishes the dimerization property of Ig-like domain 24. We previously characterized "knock-in" mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: (i) the expression level of filamin C protein is drastically reduced; (ii) mutant filamin C is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack BAG3; (iv) the expression of HSPB7 is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective filamin C dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that filamin C is important for mechanosensing in the context of Z‑disc stabilization and maintenance.

2020-09-09 | PXD020097 | Pride

Profiles of gene expression and alternative splicing in K562 cells exposed to 2 mM sodium valproate for 12 hours assessed using exon array

Project description:To investigate the effect of valproate (VPA) treatment on K562 cell line, the growth and survival of the K562 cell line were investigated using the Annexin V/PI dual staining method, and global profiles of gene expression and alternative splicing in K562 cells were assessed using exon microarray. A significant increase in cell apoptosis was observed in valproate exposed K562 cells using flow cytometry. A total of 628 transcripts were identified as being significantly differentially expressed. The number of genes demonstrating increased expression levels was greater than the number of genes demonstrating decreased expression levels (445 genes vs. 183 genes, respectively). The significant enrichment analysis of GO terms for the differentially expressed genes revealed that these genes are involved in many important biological processes such as apoptosis. Six of observed differentially expressed genes that might be involved in apoptosis were selected to undergo qRT-PCR validation. In total, 198 candidates of alternative splicing variants were identified. Among them, three alternative splicing events were selected for validation, and CBLC and TBX1 were confirmed as alternative splicing by semi-nested PCR. In conclusion, valproate exposure facilitated cell apoptosis, altered mRNA expression and alternative splicing events in the K562 cell line. Gene expression/alternative splicing in K562 cell line were measured after exposure to 2 mM valproate for 12 hours or left untreated as a control using exon array.

2011-11-11 | E-GEOD-32047 | biostudies-arrayexpress

Heart Failure Associated Changes in Alternative Splicing of Sarcomere Genes

Project description:Alternative mRNA splicing is an important mechanism for regulation of gene expression. Changes in gene expression contribute to the pathogenesis of heart failure. However, changes in mRNA splicing have not been systematically examined in heart disease. We hypothesized that mRNA splicing is changed in diseased hearts. We used the Affymetrix exon array, which separately measures expression of each known and computationally predicted exon, to globally evaluate changes in mRNA splicing in left ventricular myocardial RNA from control and ischemic cardiomyopathy (ICM) patients. We found that mRNA splicing is systematically changed in heart failure. RTPCR validated 9 previously unreported alternative splicing events. Furthermore, we demonstrated that the splicing of four key sarcomere genes, cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), myosin heavy chain 7 (MYH7), and filamin C (FLNC), was significantly altered in ICM. Altered splicing of these genes in heart disease was confirmed in independent ICM samples, and in dilated cardiomyopathy and aortic stenosis. The minor variant fraction of these five genes was sufficient to classify samples into control or disease groups with 95% accuracy. Our data indicate that alternative splicing is systematically altered in human heart disease, suggesting that disease-associated perturbation of RNA splicing may contribute to the pathogenesis and development of heart failure. Disease-related changes in splicing of sarcomere genes may directly impact cardiomyocyte function.

2010-01-11 | GSE16499 | GEO

RBM6 promotes tumor cell apoptosis and disrupts the alternative splicing of related genes in HeLa cells

Project description:RNA binding proteins have important functions in tumorigenesis; therefore, their regulatory mechanisms should be further explored. The present study aimed to determine the regulatory roles of RNA binding motif protein 6 (RBM6) in transcription and alternative splicing in Hela cells. RBM6 expression levels and its effect on the prognosis of different tumors in The Cancer Genome Atlas database were analyzed using TIMER2.0. Short hairpin RNA was used to ablate RBM6 expression in HeLa cells. Differentially expressed genes and alternative splicing events in Hela cells were assessed using RNA sequencing and quantitative real-time reverse transcription polymerase chain reaction. RBM6 was identified as a prognostic marker for bladder urothelial carcinoma, kidney renal clear cell carcinoma, mesothelioma, and pancreatic adenocarcinoma. Knockdown of RBM6 promoted cell proliferation. In Hela cells, RMB6 regulated the expression and alternative splicing of many genes involved in tumorigenesis_x001E_related pathways, including ‘apoptotic process’, ‘mitotic cell cycle’, and ‘RNA splicing’. RBM6-regulated alternatively spliced genes (DIABLO (Diablo IAP-binding mitochondrial protein), PAK4 (P21 (RAC1) activated kinase 4) and ERCC2 (ERCC excision repair 2, TFIIH core complex helicase subunit)) were subjected to quantitative real-time reverse transcription polymerase chain reaction validation, which demonstrated the same expression trends as the RNA sequencing results. Our findings showed that RBM6 affects tumorigenesis and cancer progression by disrupting alternative splicing in HeLa cells.

2023-10-17 | GSE196600 | GEO

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