scholarly journals PCBP1 regulates the transcription and alternative splicing of metastasis‑related genes and pathways in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shuai Huang ◽  
Kai Luo ◽  
Li Jiang ◽  
Xu-Dong Zhang ◽  
Ying-Hao Lv ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Rna Stability ◽  
Tumour Suppressor Gene ◽  
Convincing Evidence ◽  
Transcriptional Level ◽  
Tumour Metastasis ◽  
Significant Difference

AbstractPCBP1 is a multifunctional RNA-binding protein (RBP) expressed in most human cells and is involved in posttranscriptional gene regulation. PCBP1 regulates the alternative splicing, translation and RNA stability of many cancer-related genes and has been identified as a potential tumour suppressor gene. PCBP1 inhibits the invasion of hepatocellular carcinoma (HCC) cells, but there are few studies on the specific regulatory target and mechanism of RBPs in HCC, and it is unclear whether PCBP1 plays a role in tumour metastasis as a splicing factor. We analysed the regulation of gene expression by PCBP1 at the transcriptional level. We obtained and analysed PCBP1-knockdown RNA-seq data and eCLIP-seq data of PCBP1 in HepG2 cells and found that PCBP1 widely regulates the alternative splicing and expression of genes enriched in cancer-related pathways, including extracellular matrix, cell adhesion, small molecule metabolic process and apoptosis. We validated five regulated alternative splicing events affected by PCBP1 using RT-qPCR and found that there was a significant difference in the expression of APOC1 and SPHK1 between tumour and normal tissues. In this study, we provided convincing evidence that human PCBP1 profoundly regulates the splicing of genes associated with tumour metastasis. These findings provide new insight into potential markers or therapeutic targets for HCC treatment.

scholarly journals ELAVL1 Primarily Couples mRNA Stability with the 3’UTRs of Interferon Stimulated Genes

2020 ◽  
Author(s):  
Katherine Rothamel ◽  
Sarah Arcos ◽  
Byungil Kim ◽  
Clara Reasoner ◽  
Neelanjan Mukherjee ◽  
...  
Keyword(s):  
Rna Binding ◽  
Cytokine Production ◽  
Rna Binding Proteins ◽  
Rna Stability ◽  
Innate Immune ◽  
Transcriptional Level ◽  
Interferon Stimulated Genes ◽  
Transcriptional Regulatory ◽  
Regulatory Impact ◽  
Made In

SUMMARYUpon detection of a pathogen, the innate immune system triggers signaling events leading to the transcription of mRNAs that encode for pro-inflammatory and anti-microbial effectors. RNA-binding proteins (RBPs) interact with these functionally critical mRNAs and temporally regulate their fates at the post-transcriptional level. One such RBP is ELAVL1, which is known to bind to introns and 3’UTRs. While significant progress has been made in understanding how ELAVL1 regulates mRNAs, how its target repertoire and binding affinity changes within an immunological context remains poorly understood. Here, we overlap four distinct high-throughput approaches to define its cell-type and context-dependent targets and determine its regulatory impact during immune activation. ELAVL1 overwhelmingly binds to intronic sites in a naïve state, but during an innate immune response, ELAVL1 targets the 3’UTR - binding both previously and newly expressed mRNAs. We find that ELAVL1 mediates the RNA stability of genes that regulate the pathways involved in pathogen sensing and cytokine production. Our findings reveal the importance of examining RBP regulatory impact under dynamic transcriptomic events to best understand their post-transcriptional regulatory roles within specific biological circuitries.

scholarly journals Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Chiara Naro ◽  
Claudio Sette
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Posttranslational Modifications ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Eukaryotic Cells ◽  
Macromolecular Complex

Alternative splicing (AS) is one of the key processes involved in the regulation of gene expression in eukaryotic cells. AS catalyzes the removal of intronic sequences and the joining of selected exons, thus ensuring the correct processing of the primary transcript into the mature mRNA. The combinatorial nature of AS allows a great expansion of the genome coding potential, as multiple splice-variants encoding for different proteins may arise from a single gene. Splicing is mediated by a large macromolecular complex, the spliceosome, whose activity needs a fine regulation exerted bycis-acting RNA sequence elements andtrans-acting RNA binding proteins (RBP). The activity of both core spliceosomal components and accessory splicing factors is modulated by their reversible phosphorylation. The kinases and phosphatases involved in these posttranslational modifications significantly contribute to AS regulation and to its integration in the complex regulative network that controls gene expression in eukaryotic cells. Herein, we will review the major canonical and noncanonical splicing factor kinases and phosphatases, focusing on those whose activity has been implicated in the aberrant splicing events that characterize neoplastic transformation.

scholarly journals Long Non-coding RNA LINC01119 Promotes Neuropathic Pain by Stabilizing BDNF Transcript

2021 ◽  
Vol 14 ◽  
Author(s):  
Le Zhang ◽  
Hao Feng ◽  
Yanwu Jin ◽  
Yufeng Zhan ◽  
Qi Han ◽  
...  
Keyword(s):  
Nervous System ◽  
Neuropathic Pain ◽  
Rna Binding ◽  
Regulatory Mechanism ◽  
Rna Stability ◽  
Expression Level ◽  
Transcriptional Level ◽  
Bdnf Mrna ◽  
Protein Levels ◽  
The Central Nervous System

Neuropathic pain (NP) is caused by primary injury or dysfunction of the peripheral and the central nervous system. Long non-coding RNAs were critical regulators involved in nervous system diseases, however, the precise regulatory mechanism remains unclear. This study aims to uncover the essential role of LINC01119 in NP progression and further clarify the underlying regulatory mechanism at post-transcriptional level. LINC01119 was significantly upregulated in rats of spare nerve injury (SNI) group compared to sham group. Functionally, silencing of LINC01119 significantly alleviated the neuropathic pain-induced hypersensitivity and reduced the increase in IL−6, IL−1β, and TNF−α caused by SNI. Mechanistically, Brain-derived neurotrophic factor (BDNF) was identified as the functional target of LINC01119. Besides, an RNA binding protein, ELAVL1 could directly interact with LINC01119, and this formed LINC01119- ELAVL1 complex binds to BDNF mRNA, strengthening its RNA stability and increasing the expression level of BDNF at both transcript and protein levels. Clinically, serum LINC01119 was verified as a promising diagnostic biomarker for NP patients. LINC01119 induces NP progression via binding with ELAVL1 and increasing BDNF mRNA stability and expression level. Therefore, LINC01119 may serve as a promising diagnostic marker and therapeutic target for NP treatment.

Inhibition of translation initiation following glucose depletion in yeast facilitates a rationalization of mRNA content

2010 ◽  
Vol 38 (4) ◽  
pp. 1131-1136 ◽  
Author(s):  
Jennifer Lui ◽  
Susan G. Campbell ◽  
Mark P. Ashe
Keyword(s):  
Translation Initiation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Yeast Cells ◽  
Transcriptional Level ◽  
Diauxic Shift ◽  
P Bodies ◽  
Glucose Levels ◽  
Glucose Depletion

Glucose is the preferred carbon source for most eukaryotes and so it is important that cells can sense and react rapidly to fluctuations in glucose levels. It is becoming increasingly clear that the regulation of gene expression at the post-transcriptional level is important in the adaptation to changes in glucose levels, possibly as this could engender more rapid alterations in the concentrations of key proteins, such as metabolic enzymes. Following the removal of glucose from yeast cells a rapid inhibition of translation is observed. As a consequence, mRNPs (messenger ribonucleoproteins) relocalize into cytoplasmic granules known as P-bodies (processing bodies) and EGP-bodies. mRNA decay components localize into P-bodies, and thus these assemblies are likely to represent sites where mRNAs are targeted for degradation. In contrast, EGP-bodies lack any decay components and contain the eukaryotic translation initiation factors eIF4E, eIF4G and Pab1p, as well as other RNA-binding proteins. Therefore EGP-bodies probably constitute sites where mRNAs are earmarked for storage. So, it is possible that cells distinguish between transcripts and target them to either P-bodies or EGP-bodies depending on their functional value. The localization of mRNAs into these granules following glucose starvation may serve to preserve mRNAs that are involved in the diauxic shift to ethanol growth and entry into stationary phase, as well as to degrade mRNAs that are solely involved in glucose fermentation.

scholarly journals Regulation of Klf16 by Double Strand RNA-binding Protein STAU1 in Adipocyte Differentiation in vitro

2020 ◽  
Author(s):  
Ya Qun Guan ◽  
Xuan Yu Meng ◽  
Xiao Di Liang ◽  
Ting Ting Hu ◽  
Nurbierye Nuermamati ◽  
...  
Keyword(s):  
Rna Binding ◽  
Adipocyte Differentiation ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Adipogenic Differentiation ◽  
Regulation Of Gene Expression ◽  
Rna Binding Protein ◽  
Negative Regulator ◽  
Transcriptional Level

Abstract Background: Adipogenesis is an essential process in organismal development and plays a significant role in adipose tissue homeostasis. Post-transcriptional regulation of gene expression plays a key role in adipogenesis and involves many RNA-binding proteins (RBPs). In mammals, Staufen1 (STAU1) is a conserved RBP(RNA Binding Protein )consisting of several dsRBP (double strand RNA). STAU1 plays an important role in the Stau1-mediated mRNA decay (SMD) pathway, which is related to adipocyte formation, myocyte development, and neural differentiation. Klf16 (Kruppel like transcription factor 16) is a negative regulator that inhibits adipocyte differentiation. AIM:This study was conducted to determine the role of Klf16 in adipocyte differentiation in the context of the SMD pathway.Methods: 3T3-L1 cells were induced and cultured in vitro by cocktail method, Knockdown and Overexpression of STAU1 and KLF16. Then, adipocyte differentiation andexpression of adipogenic-related genes (STAU1, KLF16, PPARγ, and Lipin1) were measured by RT-qPCR and Western blot.RNA immunoprecipitation (RIP) method verified that STAU1 protein can bind to KLF16.Results: The results revealed that STAU1 regulates Klf16 expression at the post-transcriptional level during the adipogenic differentiation of 3T3-L1 cells.STAU1 candirectly bind the 3′UTR of Klf16 mRNA. Klf16 mRNA was found to be degraded through the SMD pathway, thus promoting adipocyte differentiation.Conclusions: In this study, the mechanism of adipocyte differentiation regulation at the post-transcriptional level is demonstrated, and Klf16 is shown as a substrate of the SMD pathway, thus providing new insights into adipogenesis.

scholarly journals Systematic Construction and Validation of an RNA-Binding Protein-Associated Model for Prognosis Prediction in Hepatocellular Carcinoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Siyuan Tian ◽  
Jingyi Liu ◽  
Keshuai Sun ◽  
Yansheng Liu ◽  
Jiahao Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Risk Score ◽  
Prognostic Model ◽  
Rna Binding ◽  
Risk Group ◽  
Clinical Stage ◽  
Cancer Genome ◽  
Clinicopathological Parameters ◽  
Transcriptional Level

BackgroundEvidence from prevailing studies show that hepatocellular carcinoma (HCC) is among the top cancers with high mortality globally. Gene regulation at post-transcriptional level orchestrated by RNA-binding proteins (RBPs) is an important mechanism that modifies various biological behaviors of HCC. Currently, it is not fully understood how RBPs affects the prognosis of HCC. In this study, we aimed to construct and validate an RBP-related model to predict the prognosis of HCC patients.MethodsDifferently expressed RBPs were identified in HCC patients based on the GSE54236 dataset from the Gene Expression Omnibus (GEO) database. Integrative bioinformatics analyses were performed to select hub genes. Gene expression patterns were validated in The Cancer Genome Atlas (TCGA) database, after which univariate and multivariate Cox regression analyses, as well as Kaplan-Meier analysis were performed to develop a prognostic model. Then, the performance of the prognostic model was assessed using receiver operating characteristic (ROC) curves and clinicopathological correlation analysis. Moreover, data from the International Cancer Genome Consortium (ICGC) database were used for external validation. Finally, a nomogram combining clinicopathological parameters and prognostic model was established for the individual prediction of survival probability.ResultsThe prognostic risk model was finally constructed based on two RBPs (BOP1 and EZH2), facilitating risk-stratification of HCC patients. Survival was markedly higher in the low-risk group relative to the high-risk group. Moreover, higher risk score was associated with advanced pathological grade and late clinical stage. Besides, the risk score was found to be an independent prognosis factor based on multivariate analysis. Nomogram including the risk score and clinical stage proved to perform better in predicting patient prognosis.ConclusionsThe RBP-related prognostic model established in this study may function as a prognostic indicator for HCC, which could provide evidence for clinical decision making.

scholarly journals Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of proteins and miRNAs

2016 ◽  
Author(s):  
Mireya Plass ◽  
Simon H. Rasmussen ◽  
Anders Krogh
Keyword(s):  
Transcriptional Regulation ◽  
Mirna Target ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Regulatory Control ◽  
Hek293 Cells ◽  
Transcriptional Level ◽  
Target Sites ◽  
Post Transcriptional Regulation

AbstractBackgroundMicroRNAs (miRNAs) are endogenous short non-coding RNAs involved in the regulation of gene expression at the post-transcriptional level typically by promoting destabilization or translational repression of target RNAs. Sometimes this regulation is absent or different, which likely is the result of interactions with other post-transcriptional factors, particularly RNA-binding proteins (RBPs). Despite the importance of the interactions between RBPs and miRNAs, little is known about how they affect post-transcriptional regulation in a global scale.ResultsIn this study, we have analyzed CLIP datasets of 49 RBPs in HEK293 cells with the aim of understanding the interplay between RBPs and miRNAs in post-transcriptional regulation. Our results show that RBPs bind preferentially in conserved regulatory hotspots that frequently contain miRNA target sites. This organization facilitates the competition and cooperation among RBPs and the regulation of miRNA target site accessibility. In some cases RBP enrichment on target sites correlates with miRNA expression, suggesting coordination between the regulatory factors. However, in most cases, competition among factors is the most plausible interpretation of our data. Upon AGO2 knockdown, transcripts that contain such hotspots that overlap target sites of expressed miRNAs in 3’UTRs are significantly less up-regulated than transcripts without them, suggesting that RBP binding limits miRNA accessibility.ConclusionsWe show that RBP binding is concentrated in regulatory hotspots in 3’UTRs. The presence of these hotspots facilitates the interaction among post-transcriptional regulators, that interact or compete with each other under different conditions. These hotspots are enriched in genes with regulatory functions such as DNA binding and RNA binding. Taken together, our results suggest that hotspots are important regulatory regions that define an extra layer of auto-regulatory control of post-transcriptional regulation.

scholarly journals Regulation of the Ras-MAPK and PI3K-mTOR Signalling Pathways by Alternative Splicing in Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Zahava Siegfried ◽  
Serena Bonomi ◽  
Claudia Ghigna ◽  
Rotem Karni
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Cellular Transformation ◽  
Signalling Pathways ◽  
Exon Definition ◽  
Extracellular Stimuli ◽  
Tumor Maintenance ◽  
Mtor Signalling

Alternative splicing is a fundamental step in regulation of gene expression of many tumor suppressors and oncogenes in cancer. Signalling through the Ras-MAPK and PI3K-mTOR pathways is misregulated and hyperactivated in most types of cancer. However, the regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing is less well established. Recent studies have shown the contribution of alternative splicing regulation of these signalling pathways which can lead to cellular transformation, cancer development, and tumor maintenance. This review will discuss findings in the literature which describe new modes of regulation of components of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing. We will also describe the mechanisms by which signals from extracellular stimuli can be communicated to the splicing machinery and to specific RNA-binding proteins that ultimately control exon definition events.

scholarly journals HSPA5 regulates the expression and alternative splicing of inflammatory and immune response genes.

2021 ◽  
Author(s):  
Heng Fan ◽  
Linping Xue ◽  
Yujin Liu ◽  
Dongmei Zuo ◽  
Fei Gao ◽  
...  
Keyword(s):  
Immune Response ◽  
Alternative Splicing ◽  
Target Genes ◽  
Rna Binding ◽  
Nf Kappa B ◽  
Immune Response Genes ◽  
Cell Proliferation And Differentiation ◽  
Transcriptional Regulatory ◽  
Significant Difference ◽  
Immune Related Genes

Abstract HSPA5 encodes a chaperone protein, BIP/GRP78, which is also an RNA-binding protein with potential transcriptional and post-transcriptional regulatory functions. To explore the functions of HSPA5 on target genes, we over-expressed HSPA5 (HSPA5-OE) in HeLa cells. Then RNA-seq analysis found 928 genes were significantly differently expressed, among which 460 genes were up-regulated and 468 genes were down-regulated in the HSPA5-OE cells. GO analysis showed that the differently expressed genes were mainly enriched in inflammation and innate Immunity responses. In addition, the up-regulated genes were enriched in the process of cell proliferation and differentiation. Immune-related pathways were also found in the DEGs with KEGG analysis. Furthermore, a total of 659 different alternative splicing events were identified based on the splicing junction reads. And the related genes were enriched in apoptosis, TNF signaling, and NF-kappa B signaling pathways. RT-qPCR experiment proved that the expression of inflammatory/immune-related genes was significantly changed with HSPA5-OE and showed significant difference in alternative splicing of genes involved in the above pathways. Our results suggest that HSPA5 regulates the expression and alternative splicing of inflammatory and immune response genes, which makes a foundation for further exploring the function of HSPA5 as RBP.

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