scholarly journals Transite: A computational motif-based analysis platform that identifies RNA-binding proteins modulating changes in gene expression

2018 ◽  
Author(s):  
Konstantin Krismer ◽  
Shohreh Varmeh ◽  
Molly A. Bird ◽  
Anna Gattinger ◽  
Yi Wen Kong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Stability ◽  
Protein Translation ◽  
State Transitions ◽  
Global Changes ◽  
Expression Data ◽  
Platinum Based Chemotherapy

AbstractRNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. In response to various stimuli, alterations in RBP function contribute to global changes in gene expression, but identifying which specific RBPs are responsible for the observed changes in gene expression patterns remains an unmet need. Here, we presentTransitea multi-pronged computational approach that systematically infers RBPs influencing gene expression changes through alterations in RNA stability and degradation. As a proof of principle, we applied Transite to public RNA expression data from human patients with non-small cell lung cancer whose tumors were sampled at diagnosis, or after recurrence following treatment with platinum-based chemotherapy. Transite implicated known RBP regulators of the DNA damage response and identified hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a generalizable framework for the identification of RBPs responsible for gene expression changes that drive cell-state transitions and adds additional value to the vast wealth of publicly-available gene expression data.

scholarly journals Comprehensive Analysis of the Functions and Prognostic Value of RNA-Binding Proteins in Thyroid Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yue Ma ◽  
Shi Yin ◽  
Xiao-feng Liu ◽  
Jing Hu ◽  
Ning Cai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Cancer ◽  
Gene Expression Data ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
Expression Data

RNA binding proteins (RBPs) have been proved to play pivotal roles in a variety types of tumors. However, there is no convincible evidence disclosing the functions of RBPs in thyroid cancer (THCA) thoroughly and systematically. Integrated analysis of the functional and prognostic effect of RBPs help better understanding tumorigenesis and development in thyroid and may provide a novel therapeutic method for THCA. In this study, we obtained a list of human RBPs from Gerstberger database, which covered 1,542 genes encoding RBPs. Gene expression data of THCA was downloaded from The Cancer Genome Atlas (TCGA, n = 567), from which we extracted 1,491 RBPs’ gene expression data. We analyzed differentially expressed RBPs using R package “limma”. Based on differentially expressed RBPs, we constructed protein-protein interaction network and the GO and KEGG pathway enrichment analyses were carried out. We found six RBPs (AZGP1, IGF2BP2, MEX3A, NUDT16, NUP153, USB1) independently associated with prognosis of patients with thyroid cancer according to univariate and multivariate Cox proportional hazards regression models. The survival analysis and risk score analysis achieved good performances from this six-gene prognostic model. Nomogram was constructed to guide clinical decision in practice. Finally, biological experiments disclosed that NUP153 and USB1 can significantly impact cancer cell proliferation and migration. In conclusion, our research provided a new insight of thyroid tumorigenesis and development based on analyses of RBPs. More importantly, the six-gene model may play an important role in clinical practice in the future.

The Therapeutic Potential and Role of miRNA, lncRNA, and circRNA in Osteoarthritis

2019 ◽  
Vol 19 (4) ◽  
pp. 255-263 ◽  
Author(s):  
Yuangang Wu ◽  
Xiaoxi Lu ◽  
Bin Shen ◽  
Yi Zeng
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Extracellular Matrix ◽  
Inflammatory Reaction ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Translation ◽  
Cochrane Library

Background: Osteoarthritis (OA) is a disease characterized by progressive degeneration, joint hyperplasia, narrowing of joint spaces, and extracellular matrix metabolism. Recent studies have shown that the pathogenesis of OA may be related to non-coding RNA, and its pathological mechanism may be an effective way to reduce OA. Objective: The purpose of this review was to investigate the recent progress of miRNA, long noncoding RNA (lncRNA) and circular RNA (circRNA) in gene therapy of OA, discussing the effects of this RNA on gene expression, inflammatory reaction, apoptosis and extracellular matrix in OA. Methods: The following electronic databases were searched, including PubMed, EMBASE, Web of Science, and the Cochrane Library, for published studies involving the miRNA, lncRNA, and circRNA in OA. The outcomes included the gene expression, inflammatory reaction, apoptosis, and extracellular matrix. Results and Discussion: With the development of technology, miRNA, lncRNA, and circRNA have been found in many diseases. More importantly, recent studies have found that RNA interacts with RNA-binding proteins to regulate gene transcription and protein translation, and is involved in various pathological processes of OA, thus becoming a potential therapy for OA. Conclusion: In this paper, we briefly introduced the role of miRNA, lncRNA, and circRNA in the occurrence and development of OA and as a new target for gene therapy.

scholarly journals The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 552
Author(s):  
Jasmine Harley ◽  
Benjamin E. Clarke ◽  
Rickie Patani
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Mitochondrial Dysfunction ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Therapeutic Strategies ◽  
Lateral Sclerosis

RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.

scholarly journals Long noncoding RNAs as tumorigenic factors and therapeutic targets for renal cell carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Haiyan Shen ◽  
Guomin Luo ◽  
Qingjuan Chen
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Noncoding Rnas ◽  
Protein Translation ◽  
Long Noncoding Rnas ◽  
In Vivo Studies

AbstractApproximately 338,000 patients are diagnosed with kidney cancer worldwide each year, and renal cell carcinoma (RCC), which is derived from renal epithelium, accounts for more than ninety percent of the malignancy. Next generation RNA sequencing has enabled the identification of novel long noncoding RNAs (lncRNAs) in the past 10 years. Recent studies have provided extensive evidence that lncRNAs bind to chromatin modification proteins, transcription factors, RNA-binding proteins and microRNAs, and thereby modulate gene expression through regulating chromatin status, gene transcription, pre-mRNA splicing, mRNA decay and stability, protein translation and stability. In vitro and in vivo studies have demonstrated that over-expression of oncogenic lncRNAs and silencing of tumor suppressive lncRNAs are a common feature of human RCC, and that aberrant lncRNA expression is a marker for poor patient prognosis, and is essential for the initiation and progression of RCC. Because lncRNAs, compared with mRNAs, are expressed in a tissue-specific manner, aberrantly expressed lncRNAs can be better targeted for the treatment of RCC through screening small molecule compounds which block the interaction between lncRNAs and their binding proteins or microRNAs.

scholarly journals The Role of RNA-Binding Proteins in Vertebrate Neural Crest and Craniofacial Development

2021 ◽  
Vol 9 (3) ◽  
pp. 34
Author(s):  
Thomas E. Forman ◽  
Brenna J. C. Dennison ◽  
Katherine A. Fantauzzo
Keyword(s):  
Gene Expression ◽  
Neural Crest ◽  
Binding Proteins ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Craniofacial Development ◽  
Specific Sequence ◽  
Altered Expression ◽  
Binding Domains

Cranial neural crest (NC) cells delaminate from the neural folds in the forebrain to the hindbrain during mammalian embryogenesis and migrate into the frontonasal prominence and pharyngeal arches. These cells generate the bone and cartilage of the frontonasal skeleton, among other diverse derivatives. RNA-binding proteins (RBPs) have emerged as critical regulators of NC and craniofacial development in mammals. Conventional RBPs bind to specific sequence and/or structural motifs in a target RNA via one or more RNA-binding domains to regulate multiple aspects of RNA metabolism and ultimately affect gene expression. In this review, we discuss the roles of RBPs other than core spliceosome components during human and mouse NC and craniofacial development. Where applicable, we review data on these same RBPs from additional vertebrate species, including chicken, Xenopus and zebrafish models. Knockdown or ablation of several RBPs discussed here results in altered expression of transcripts encoding components of developmental signaling pathways, as well as reduced cell proliferation and/or increased cell death, indicating that these are common mechanisms contributing to the observed phenotypes. The study of these proteins offers a relatively untapped opportunity to provide significant insight into the mechanisms underlying gene expression regulation during craniofacial morphogenesis.

scholarly journals RNA-binding proteins regulate aldosterone homeostasis in human steroidogenic cells

2021 ◽  
Author(s):  
Rui Fu ◽  
Kimberly Wellman ◽  
Amber Baldwin ◽  
Juilee Rege ◽  
Kathryn Walters ◽  
...  
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Ex Vivo ◽  
Human Cell Line ◽  
Rna Decay ◽  
Type I ◽  
Aldosterone Production

ABSTRACTAngiotensin II (AngII) binds to the type I angiotensin receptor in the adrenal cortex to initiate a cascade of events leading to the production of aldosterone, a master regulator of blood pressure. Despite extensive characterization of the transcriptional and enzymatic control of adrenocortical steroidogenesis, there are still major gaps in our knowledge related to precise regulation of AII-induced gene expression kinetics. Specifically, we do not know the regulatory contribution of RNA-binding proteins (RBPs) and RNA decay, which can control the timing of stimulus-induced gene expression. To investigate this question, we performed a high-resolution RNA-seq time course of the AngII stimulation response and 4-thiouridine pulse labeling in a steroidogenic human cell line (H295R). We identified twelve temporally distinct gene expression responses that contained mRNA encoding proteins known to be important for various steps of aldosterone production, such as cAMP signaling components and steroidogenic enzymes. AngII response kinetics for many of these mRNAs revealed a coordinated increase in both synthesis and decay. These findings were validated in primary human adrenocortical cells stimulated ex vivo with AngII. Using a candidate siRNA screen, we identified a subset of RNA-binding protein and RNA decay factors that activate or repress AngII-stimulated aldosterone production. Among the repressors of aldosterone were BTG2, which promotes deadenylation and global RNA decay. BTG2 was induced in response to AngII stimulation and promoted the repression of mRNAs encoding pro-steroidogenic factors indicating the existence of an incoherent feedforward loop controlling aldosterone homeostasis. Together, these data support a model in which coordinated increases in transcription and regulated RNA decay facilitates the major transcriptomic changes required to implement a pro-steroidogenic gene expression program that is temporally restricted to prevent aldosterone overproduction.

piRNAs Interact with Cold-Shock Domain-Containing RNA Binding Proteins and Regulate Neuronal Gene Expression During Differentiation

2022 ◽  
Author(s):  
Charannya Sozheesvari Subhramanyam ◽  
Qiong Cao ◽  
Cheng Wang ◽  
Zealyn Shi-Lin Heng ◽  
Zhihong Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Cold Shock ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neuronal Gene ◽  
Cold Shock Domain

The expanding world of metabolic enzymes moonlighting as RNA binding proteins

2021 ◽  
Author(s):  
Nicole J. Curtis ◽  
Constance J. Jeffery
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Molecular Structures ◽  
Intermediary Metabolism ◽  
The Many ◽  
And Function

RNA binding proteins play key roles in many aspects of RNA metabolism and function, including splicing, transport, translation, localization, stability and degradation. Within the past few years, proteomics studies have identified dozens of enzymes in intermediary metabolism that bind to RNA. The wide occurrence and conservation of RNA binding ability across distant branches of the evolutionary tree suggest that these moonlighting enzymes are involved in connections between intermediary metabolism and gene expression that comprise far more extensive regulatory networks than previously thought. There are many outstanding questions about the molecular structures and mechanisms involved, the effects of these interactions on enzyme and RNA functions, and the factors that regulate the interactions. The effects on RNA function are likely to be wider than regulation of translation, and some enzyme–RNA interactions have been found to regulate the enzyme's catalytic activity. Several enzyme–RNA interactions have been shown to be affected by cellular factors that change under different intracellular and environmental conditions, including concentrations of substrates and cofactors. Understanding the molecular mechanisms involved in the interactions between the enzymes and RNA, the factors involved in regulation, and the effects of the enzyme–RNA interactions on both the enzyme and RNA functions will lead to a better understanding of the role of the many newly identified enzyme–RNA interactions in connecting intermediary metabolism and gene expression.

scholarly journals The structural basis for RNA selectivity by the IMP family of RNA-binding proteins

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jeetayu Biswas ◽  
Vivek L. Patel ◽  
Varun Bhaskar ◽  
Jeffrey A. Chao ◽  
Robert H. Singer ◽  
...  
Keyword(s):  
Neural Development ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Stability ◽  
Underlying Mechanism ◽  
Structural Basis ◽  
General Mechanism ◽  
Binding Domains ◽  
Variable Loops

Abstract The IGF2 mRNA-binding proteins (ZBP1/IMP1, IMP2, IMP3) are highly conserved post-transcriptional regulators of RNA stability, localization and translation. They play important roles in cell migration, neural development, metabolism and cancer cell survival. The knockout phenotypes of individual IMP proteins suggest that each family member regulates a unique pool of RNAs, yet evidence and an underlying mechanism for this is lacking. Here, we combine systematic evolution of ligands by exponential enrichment (SELEX) and NMR spectroscopy to demonstrate that the major RNA-binding domains of the two most distantly related IMPs (ZBP1 and IMP2) bind to different consensus sequences and regulate targets consistent with their knockout phenotypes and roles in disease. We find that the targeting specificity of each IMP is determined by few amino acids in their variable loops. As variable loops often differ amongst KH domain paralogs, we hypothesize that this is a general mechanism for evolving specificity and regulation of the transcriptome.

A Potential Therapeutic Target RNA-binding Protein, Arid5a for the Treatment of Inflammatory Disease Associated with Aberrant Cytokine Expression

2018 ◽  
Vol 24 (16) ◽  
pp. 1766-1771 ◽  
Author(s):  
Kazuya Masuda ◽  
Tadamitsu Kishimoto
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Severe Sepsis ◽  
Inflammatory Cytokines ◽  
Binding Proteins ◽  
Rna Binding ◽  
Cytokine Production ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Transcriptional Level

Background: Infection, tissue damage and aging can cause inflammation with high levels of inflammatory cytokines. Overproduction of inflammatory cytokines often leads to systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock. However, prominent therapeutic targets have not been found, although the incidence of sepsis is likely to increase annually. Our recent studies indicate that some RNA-binding proteins, which control gene expression of inflammatory cytokines at the post-transcriptional level, may play a critical role in inflammatory diseases such as sepsis. Results: 1) One of the RNA-binding proteins, AT-rich interactive domain-containing 5a (Arid5a) promotes cytokine production through control of mRNA half-lives of pro-inflammatory molecules such as IL-6, STAT3, T-bet, and OX40 in activated macrophages and T cells. Arid5a KO mice are refractory to endotoxin shock, bleomycininduced lung injury, and inflammatory autoimmune disease. 2) Chlorpromazine (CPZ), which is recognized as a psychotic drug, impairs post-transcriptional gene expression of Il6 in LPS-stimulated macrophages: CPZ inhibits the binding activity of Arid5a to the 3’UTR of Il6 mRNA, thereby destabilizing Il6 mRNA possibly through suppression of Arid5a expression. 3) CPZ has strong suppressive effects on cytokine production such as TNF-α in vivo. Mice with treatment of CPZ are resistant to lipopolysaccharide (LPS)-induced shock. Conclusion: Thus, Arid5a contributes to the activation of macrophages and T cells through positive control of mRNA half-lives of inflammatory cytokines and its related molecules, which might lead to cytokine storm. Interestingly, Arid5a was identified from an inhibitory effect of CPZ on IL-6 production in macrophages activated by LPS. Therefore, CPZ derivatives or Arid5a inhibitors may have a potential to suppress severe sepsis through control of post-transcriptional gene expression.

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