scholarly journals Human cells contain myriad excised linear intron RNAs with potential functions in gene regulation and as disease biomarkers

2020 ◽  
Author(s):  
Jun Yao ◽  
Hengyi Xu ◽  
Shelby Winans ◽  
Douglas C. Wu ◽  
Manuel Ares ◽  
...  
Keyword(s):  
Stress Responses ◽  
Rna Splicing ◽  
Growth Regulation ◽  
Rna Binding ◽  
Human Cells ◽  
Breast Cancer Patients ◽  
Regulatory Pathways ◽  
Cellular Stress Responses ◽  
Cell Type Specific ◽  
And Function

AbstractWe used thermostable group II intron reverse transcriptase sequencing (TGIRT-seq), which gives full-length end-to-end sequence reads of structured RNAs, to identify > 8,500 short fulllength excised linear intron (FLEXI) RNAs originating from > 3,500 different genes in human cells and tissues. Most FLEXI RNAs have stable predicted secondary structures, making them difficult to detect by other methods. Some FLEXI RNAs corresponded to annotated mirtron pre-miRNAs (introns that are processed by DICER into functional miRNAs) or agotrons (introns that bind AGO2 and function in a miRNA-like manner) and a few encode snoRNAs. However, the vast majority had not been characterized previously. FLEXI RNA profiles were cell-type specific, reflecting differences in host gene transcription, alternative splicing, and intron RNA turnover, and comparisons of matched tumor and healthy tissues from breast cancer patients and cell lines revealed hundreds of differences in FLEXI RNA expression. About half of the FLEXI RNAs contained an experimentally identified binding site for one or more proteins in published CLIP-seq datasets. In addition to proteins that have RNA splicing-or miRNA-related functions, proteins that bind ≥ 30 different FLEXI RNAs included transcription factors, chromatin remodeling proteins, and proteins involved in cellular stress responses and growth regulation, potentially linking FLEXI RNA binding to these processes. Our findings suggest previously unsuspected connections between intron RNAs and cellular regulatory pathways and identify a large new class of RNAs that may serve as broadly applicable biomarkers for human diseases.

scholarly journals Novel Insights into YB-1 Signaling and Cell Death Decisions

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3306
Author(s):  
Aneri Shah ◽  
Jonathan A. Lindquist ◽  
Lars Rosendahl ◽  
Ingo Schmitz ◽  
Peter R. Mertens
Keyword(s):  
Stress Responses ◽  
Rna Splicing ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Inflammatory Responses ◽  
Rna Binding Proteins ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Tumor Therapy ◽  
Inflammatory Microenvironment

YB-1 belongs to the evolutionarily conserved cold-shock domain protein family of RNA binding proteins. YB-1 is a well-known transcriptional and translational regulator, involved in cell cycle progression, DNA damage repair, RNA splicing, and stress responses. Cell stress occurs in many forms, e.g., radiation, hyperthermia, lipopolysaccharide (LPS) produced by bacteria, and interferons released in response to viral infection. Binding of the latter factors to their receptors induces kinase activation, which results in the phosphorylation of YB-1. These pathways also activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a well-known transcription factor. NF-κB is upregulated following cellular stress and orchestrates inflammatory responses, cell proliferation, and differentiation. Inflammation and cancer are known to share common mechanisms, such as the recruitment of infiltrating macrophages and development of an inflammatory microenvironment. Several recent papers elaborate the role of YB-1 in activating NF-κB and signaling cell survival. Depleting YB-1 may tip the balance from survival to enhanced apoptosis. Therefore, strategies that target YB-1 might be a viable therapeutic option to treat inflammatory diseases and improve tumor therapy.

scholarly journals Function of Circular RNAs in Fish and Their Potential Application as Biomarkers

2021 ◽  
Vol 22 (13) ◽  
pp. 7119
Author(s):  
Golam Rbbani ◽  
Artem Nedoluzhko ◽  
Jorge Galindo-Villegas ◽  
Jorge M. O. Fernandes
Keyword(s):  
Growth Regulation ◽  
Functional Characterization ◽  
Circular Rnas ◽  
Farmed Fish ◽  
Developmentally Regulated ◽  
Specific Expression ◽  
Cell Type Specific Expression ◽  
Cell Type Specific ◽  
Taxonomic Groups ◽  
And Function

Circular RNAs (circRNAs) are an emerging class of regulatory RNAs with a covalently closed-loop structure formed during pre-mRNA splicing. Recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of novel approaches to their identification and functional characterization. CircRNAs are stable, developmentally regulated, and show tissue- and cell-type-specific expression across different taxonomic groups. They play a crucial role in regulating various biological processes at post-transcriptional and translational levels. However, the involvement of circRNAs in fish immunity has only recently been recognized. There is also broad evidence in mammals that the timely expression of circRNAs in muscle plays an essential role in growth regulation but our understanding of their expression and function in teleosts is still very limited. Here, we discuss the available knowledge about circRNAs and their role in growth and immunity in vertebrates from a comparative perspective, with emphasis on cultured teleost fish. We expect that the interest in teleost circRNAs will increase substantially soon, and we propose that they may be used as biomarkers for selective breeding of farmed fish, thus contributing to the sustainability of the aquaculture sector.

scholarly journals Rho GTPases: Big Players in Breast Cancer Initiation, Metastasis and Therapeutic Responses

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2167
Author(s):  
Brock Humphries ◽  
Zhishan Wang ◽  
Chengfeng Yang
Keyword(s):  
Breast Cancer ◽  
Membrane Trafficking ◽  
Rho Gtpases ◽  
Migration And Invasion ◽  
Breast Cancer Patients ◽  
Cancer Initiation ◽  
Cell Type Specific ◽  
And Function ◽  
Therapeutic Responses

Rho GTPases, a family of the Ras GTPase superfamily, are key regulators of the actin cytoskeleton. They were originally thought to primarily affect cell migration and invasion; however, recent advances in our understanding of the biology and function of Rho GTPases have demonstrated their diverse roles within the cell, including membrane trafficking, gene transcription, migration, invasion, adhesion, survival and growth. As these processes are critically involved in cancer initiation, metastasis and therapeutic responses, it is not surprising that studies have demonstrated important roles of Rho GTPases in cancer. Although the majority of data indicates an oncogenic role of Rho GTPases, tumor suppressor functions of Rho GTPases have also been revealed, suggesting a context and cell-type specific function for Rho GTPases in cancer. This review aims to summarize recent progresses in our understanding of the regulation and functions of Rho GTPases, specifically in the context of breast cancer. The potential of Rho GTPases as therapeutic targets and prognostic tools for breast cancer patients are also discussed.

scholarly journals Deep analysis of RNA N6-adenosine methylation (m6A) patterns in human cells

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Jun Wang ◽  
Liangjiang Wang
Keyword(s):  
Rna Binding ◽  
Data Transfer ◽  
Rna Binding Proteins ◽  
Consensus Sequence ◽  
Model Performance ◽  
Cell Types ◽  
Human Cells ◽  
Rna Modification ◽  
Cell Type ◽  
Cell Type Specific

Abstract N6-adenosine methylation (m6A) is the most abundant internal RNA modification in eukaryotes, and affects RNA metabolism and non-coding RNA function. Previous studies suggest that m6A modifications in mammals occur on the consensus sequence DRACH (D = A/G/U, R = A/G, H = A/C/U). However, only about 10% of such adenosines can be m6A-methylated, and the underlying sequence determinants are still unclear. Notably, the regulation of m6A modifications can be cell-type-specific. In this study, we have developed a deep learning model, called TDm6A, to predict RNA m6A modifications in human cells. For cell types with limited availability of m6A data, transfer learning may be used to enhance TDm6A model performance. We show that TDm6A can learn common and cell-type-specific motifs, some of which are associated with RNA-binding proteins previously reported to be m6A readers or anti-readers. In addition, we have used TDm6A to predict m6A sites on human long non-coding RNAs (lncRNAs) for selection of candidates with high levels of m6A modifications. The results provide new insights into m6A modifications on human protein-coding and non-coding transcripts.

scholarly journals Deficiency in the double-stranded RNA binding protein HYPONASTIC LEAVES1 increases sensitivity to the endoplasmic reticulum stress inducer tunicamycin in Arabidopsis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Rikako Hirata ◽  
Kei-ichiro Mishiba ◽  
Nozomu Koizumi ◽  
Yuji Iwata
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Stress Responses ◽  
Rna Binding ◽  
Transcriptional Response ◽  
Mirna Biogenesis ◽  
Loss Of Function ◽  
Wild Type ◽  
Protein Coding ◽  
And Function

Abstract Objective microRNA (miRNA) is a small non-coding RNA that regulates gene expression by sequence-dependent binding to protein-coding mRNA in eukaryotic cells. In plants, miRNA plays important roles in a plethora of physiological processes, including abiotic and biotic stress responses. The present study was conducted to investigate whether miRNA-mediated regulation is important for the endoplasmic reticulum (ER) stress response in Arabidopsis. Results We found that hyl1 mutant plants are more sensitive to tunicamycin, an inhibitor of N-linked glycosylation that causes ER stress than wild-type plants. Other miRNA-related mutants, se and ago1, exhibited similar sensitivity to the wild-type, indicating that the hypersensitive phenotype is attributable to the loss-of-function of HYL1, rather than deficiency in general miRNA biogenesis and function. However, the transcriptional response of select ER stress-responsive genes in hyl1 mutant plants was indistinguishable from that of wild-type plants, suggesting that the loss-of-function of HYL1 does not affect the ER stress signaling pathways.

scholarly journals Plasticity of nuclear and cytoplasmic stress responses of RNA-binding proteins

2020 ◽  
Vol 48 (9) ◽  
pp. 4725-4740 ◽  
Author(s):  
Michael Backlund ◽  
Frank Stein ◽  
Mandy Rettel ◽  
Thomas Schwarzl ◽  
Joel I Perez-Perri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Stress Responses ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Environmental Cues ◽  
Adaptive Responses ◽  
Stressed Cells ◽  
And Function

Abstract Cellular stress causes multifaceted reactions to trigger adaptive responses to environmental cues at all levels of the gene expression pathway. RNA-binding proteins (RBP) are key contributors to stress-induced regulation of RNA fate and function. Here, we uncover the plasticity of the RNA interactome in stressed cells, differentiating between responses in the nucleus and in the cytoplasm. We applied enhanced RNA interactome capture (eRIC) analysis preceded by nucleo-cytoplasmic fractionation following arsenite-induced oxidative stress. The data reveal unexpectedly compartmentalized RNA interactomes and their responses to stress, including differential responses of RBPs in the nucleus versus the cytoplasm, which would have been missed by whole cell analyses.

scholarly journals Regulation and Function of RNA Pseudouridylation in Human Cells

2020 ◽  
Vol 54 (1) ◽  
pp. 309-336
Author(s):  
Erin K. Borchardt ◽  
Nicole M. Martinez ◽  
Wendy V. Gilbert
Keyword(s):  
Messenger Rna ◽  
Noncoding Rna ◽  
Protein Production ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Cells ◽  
Rna Sequences ◽  
Rna Targets ◽  
Pseudouridine Synthases ◽  
And Function

Recent advances in pseudouridine detection reveal a complex pseudouridine landscape that includes messenger RNA and diverse classes of noncoding RNA in human cells. The known molecular functions of pseudouridine, which include stabilizing RNA conformations and destabilizing interactions with varied RNA-binding proteins, suggest that RNA pseudouridylation could have widespread effects on RNA metabolism and gene expression. Here, we emphasize how much remains to be learned about the RNA targets of human pseudouridine synthases, their basis for recognizing distinct RNA sequences, and the mechanisms responsible for regulated RNA pseudouridylation. We also examine the roles of noncoding RNA pseudouridylation in splicing and translation and point out the potential effects of mRNA pseudouridylation on protein production, including in the context of therapeutic mRNAs.

scholarly journals RALF1-FERONIA complex affects splicing dynamics to modulate stress responses and growth in plants

2020 ◽  
Vol 6 (21) ◽  
pp. eaaz1622 ◽  
Author(s):  
Long Wang ◽  
Tao Yang ◽  
Bingqian Wang ◽  
Qinlu Lin ◽  
Sirui Zhu ◽  
...  
Keyword(s):  
Stress Responses ◽  
Rna Splicing ◽  
Rna Binding ◽  
Fine Tuning ◽  
Nuclear Accumulation ◽  
Nonsense Mediated Decay ◽  
Rapid Alkalinization Factor ◽  
Transcriptomic Changes ◽  
Mrna Binding ◽  
External Stimuli

The environmentally responsive signaling pathways that link global transcriptomic changes through alternative splicing (AS) to plant fitness remain unclear. Here, we found that the interaction of the extracellular rapid alkalinization FACTOR 1 (RALF1) peptide with its receptor FERONIA (FER) triggered a rapid and massive RNA AS response by interacting with and phosphorylating glycine-rich RNA binding protein7 (GRP7) to elevate GRP7 nuclear accumulation in Arabidopsis thaliana. FER-dependent GRP7 phosphorylation enhanced its mRNA binding ability and its association with the spliceosome component U1-70K to enable splice site selection, modulating dynamic AS. Genetic reversal of a RALF1-FER–dependent splicing target partly rescued mutants deficient in GRP7. AS of GRP7 itself induced nonsense-mediated decay feedback to the RALF1-FER-GRP7 module, fine-tuning stress responses, and cell growth. The RALF1-FER-GRP7 module provides a paradigm for regulatory mechanisms of RNA splicing in response to external stimuli.

scholarly journals CFM9, a Mitochondrial CRM Protein, Is Crucial for Mitochondrial Intron Splicing, Mitochondria Function and Arabidopsis Growth and Stress Responses

2019 ◽  
Vol 60 (11) ◽  
pp. 2538-2548 ◽  
Author(s):  
Kwanuk Lee ◽  
Su Jung Park ◽  
Youn-Il Park ◽  
Hunseung Kang
Keyword(s):  
Stress Responses ◽  
Rna Splicing ◽  
Growth Defect ◽  
Wild Type ◽  
Respiration Activity ◽  
Abnormal Mitochondria ◽  
Chloroplast Rna ◽  
And Function ◽  
Mitochondrial Introns

Abstract Although the importance of chloroplast RNA splicing and ribosome maturation (CRM) domain-containing proteins has been established for chloroplast RNA metabolism and plant development, the functional role of CRM proteins in mitochondria remains largely unknown. Here, we investigated the role of a mitochondria-targeted CRM protein (At3g27550), named CFM9, in Arabidopsis thaliana. Confocal analysis revealed that CFM9 is localized in mitochondria. The cfm9 mutant exhibited delayed seed germination, retarded growth and shorter height compared with the wild type under normal conditions. The growth-defect phenotypes were more manifested upon high salinity, dehydration or ABA application. Complementation lines expressing CFM9 in the mutant background fully recovered the wild-type phenotypes. Notably, the mutant had abnormal mitochondria, increased hydrogen peroxide and reduced respiration activity, implying that CFM9 is indispensable for normal mitochondrial function. More important, the splicing of many intron-containing genes in mitochondria was defective in the mutant, suggesting that CFM9 plays a crucial role in the splicing of mitochondrial introns. Collectively, our results provide clear evidence emphasizing that CFM9 is an essential factor in the splicing of mitochondrial introns, which is crucial for mitochondrial biogenesis and function and the growth and development of Arabidopsis.

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