Aberrant RNA Splicing Events Driven by Mutations of RNA-Binding Proteins as Indicators for Skin Cutaneous Melanoma Prognosis

Abstract Recent reports have revealed that repeat-derived sequences embedded in introns or long noncoding RNAs (lncRNAs) are targets of RNA-binding proteins (RBPs) and contribute to biological processes such as RNA splicing or transcriptional regulation. These findings suggest that repeat-derived RNAs are important as scaffolds of RBPs and functional elements. However, the overall functional sequences of the repeat-derived RNAs are not fully understood. Here, we show the putative functional repeat-derived RNAs by analyzing the binding patterns of RBPs based on ENCODE eCLIP data. We mapped all eCLIP reads to repeat sequences and observed that 10.75 % and 7.04 % of reads on average were enriched (at least 2-fold over control) in the repeats in K562 and HepG2 cells, respectively. Using these data, we predicted functional RNA elements on the sense and antisense strands of long interspersed element 1 (LINE1) sequences. Furthermore, we found several new sets of RBPs on fragments derived from other transposable element (TE) families. Some of these fragments show specific and stable secondary structures and are found to be inserted into the introns of genes or lncRNAs. These results suggest that the repeat-derived RNA sequences are strong candidates for the functional RNA elements of endogenous noncoding RNAs.

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RNA-Binding Proteins as Targets to Improve Salt Stress Tolerance in Crops

Agronomy ◽

10.3390/agronomy10020250 ◽

2020 ◽

Vol 10 (2) ◽

pp. 250 ◽

Cited By ~ 2

Author(s):

Sara Rosa Téllez ◽

Rodoldphe Kanhonou ◽

Carlos Castellote Bellés ◽

Ramón Serrano ◽

Paula Alepuz ◽

...

Keyword(s):

Salt Stress ◽

Salt Tolerance ◽

Sugar Beet ◽

Rna Splicing ◽

Yeast Strain ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Crop Improvement ◽

Salt Toxicity

Salt stress drastically reduce crop productivity. In order to identify genes that could improve crop salt tolerance, we randomly expressed a cDNA library of the halotolerant sugar beet in a sodium-sensitive yeast strain. We identified six sugar beet genes coding for RNA binding proteins (RBP) able to increase the yeast Na+-tolerance. Two of these genes, named Beta vulgaris Salt Tolerant 3 (BvSATO3) and BvU2AF35b, participate in RNA splicing. The other four BvSATO genes (BvSATO1, BvSATO2, BvSATO4 and BvSATO6) are putatively involved in other processes of RNA metabolism. BvU2AF35b improved the growth of a wild type yeast strain under salt stress, and also in mutant backgrounds with impaired splicing, thus confirming that splicing is a target of salt toxicity. To validate the yeast approach, we characterized BvSATO1 in sugar beet and Arabidopsis. BvSATO1 expression was repressed by salt treatment in sugar beet, suggesting that this gene could be a target of salt toxicity. Expression of BvSATO1 in Arabidopsis increased the plant salt tolerance. Our results suggest that not only RNA splicing, but RNA metabolic processes such as such as RNA stability or nonsense-mediated mRNA decay may also be affected by salt stress and could be biotechnological targets for crop improvement.

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Comprehensive analysis of differences of N6-methyladenosine RNA methylomes between high-fat-fed and normal mouse livers

Epigenomics ◽

10.2217/epi-2019-0009 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1267-1282 ◽

Cited By ~ 12

Author(s):

Zupeng Luo ◽

Zhiwang Zhang ◽

Lina Tai ◽

Lifang Zhang ◽

Zheng Sun ◽

...

Keyword(s):

Fatty Liver ◽

High Fat Diet ◽

Rna Splicing ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Normal Liver ◽

Comprehensive Analysis ◽

Control Group ◽

High Fat

Aim: To assess the m6A methylome in mouse fatty liver induced by a high-fat diet (HFD). Materials & methods: MeRIP-seq was performed to identify differences in the m6A methylomes between the normal liver and fatty liver induced by an HFD. Results: As compared with the control group, the upmethylated coding genes upon feeding an HFD were primarily enriched in processes associated with lipid metabolism, while genes with downmethylation were enriched in processes associated with metabolism and translation. Furthermore, many RNA-binding proteins that potentially bind to differentially methylated m6A sites were mainly annotated in processes of RNA splicing. Conclusion: These findings suggest that differential m6A methylation may act on functional genes through RNA-binding proteins to regulate the metabolism of lipids in fatty liver disease.

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The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells

Molecular and Cellular Biology ◽

10.1128/mcb.01604-12 ◽

2013 ◽

Vol 33 (6) ◽

pp. 1233-1243 ◽

Cited By ~ 47

Author(s):

Yunling Wang ◽

Gillian Vogel ◽

Zhenbao Yu ◽

Stéphane Richard

Keyword(s):

Glial Cells ◽

Rna Splicing ◽

Cellular Localization ◽

Binding Proteins ◽

Rna Binding ◽

Egf Receptor ◽

Cell Function ◽

Rna Binding Proteins ◽

Glioblastoma Cells ◽

Egfr Expression

Thequaking(qkI) gene encodes 3 major alternatively spliced isoforms that contain unique sequences at their C termini dictating their cellular localization. QKI-5 is predominantly nuclear, whereas QKI-6 is distributed throughout the cell and QKI-7 is cytoplasmic. The QKI isoforms are sequence-specific RNA binding proteins expressed mainly in glial cells modulating RNA splicing, export, and stability. Herein, we identify a new role for the QKI proteins in the regulation of microRNA (miRNA) processing. We observed that small interfering RNA (siRNA)-mediated QKI depletion of U343 glioblastoma cells leads to a robust increase in miR-7 expression. The processing from primary to mature miR-7 was inhibited in the presence QKI-5 and QKI-6 but not QKI-7, suggesting that the nuclear localization plays an important role in the regulation of miR-7 expression. The primary miR-7-1 was bound by the QKI isoforms in a QKI response element (QRE)-specific manner. We observed that the pri-miR-7-1 RNA was tightly bound to Drosha in the presence of the QKI isoforms, and this association was not observed in siRNA-mediated QKI or Drosha-depleted U343 glioblastoma cells. Moreover, the presence of the QKI isoforms led to an increase presence of pri-miR-7 in nuclear foci, suggesting that pri-miR-7-1 is retained in the nucleus by the QKI isoforms. miR-7 is known to target the epidermal growth factor (EGF) receptor (EGFR) 3′ untranslated region (3′-UTR), and indeed, QKI-deficient U343 cells had reduced EGFR expression and decreased ERK activation in response to EGF. Elevated levels of miR-7 are associated with cell cycle arrest, and it was observed that QKI-deficient U343 that harbor elevated levels of miR-7 exhibited defects in cell proliferation that were partially rescued by the addition of a miR-7 inhibitor. These findings suggest that the QKI isoforms regulate glial cell function and proliferation by regulating the processing of certain miRNAs.

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Genomic sequences and RNA binding proteins predict RNA splicing kinetics in various single-cell contexts

10.1101/2021.05.02.442314 ◽

2021 ◽

Author(s):

Ruiyan Hou ◽

Yuanhua Huang

Keyword(s):

Single Cell ◽

Rna Splicing ◽

Binding Proteins ◽

Rna Binding ◽

Genomic Sequence ◽

Rna Binding Proteins ◽

Single Cells ◽

Regulatory Machinery ◽

Kinetic Rates ◽

Splicing Efficiency

RNA splicing is a key step of gene expression in higher organisms. Accurate quantification of the two-step splicing kinetics is of high interests not only for understanding the regulatory machinery, but also for estimating the RNA velocity in single cells. However, the kinetic rates remain poorly understood due to the intrinsic low content of unspliced RNAs and its stochasticity across contexts. Here, we estimated the relative splicing efficiency across a variety of single-cell RNA-Seq data with scVelo. We further extracted three large feature sets including 92 basic genomic sequence features, 65,536 octamers and 120 RNA binding proteins features and found they are highly predictive to RNA splicing efficiency across multiple tissues on human and mouse. A set of important features have been identified with strong regulatory potentials on splicing efficiency. This predictive power brings promise to reveal the complexity of RNA processing and to enhance the estimation of single-cell RNA velocity.

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Distinct roles of hnRNPH1 low-complexity domains in splicing and transcription

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2109668118 ◽

2021 ◽

Vol 118 (50) ◽

pp. e2109668118

Author(s):

Ga Hye Kim ◽

Ilmin Kwon

Keyword(s):

Phase Separation ◽

Transcriptional Activation ◽

Rna Splicing ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Lymphoblastic Leukemia ◽

Large Family ◽

Low Complexity ◽

Reversible Polymers

Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins that control key events in RNA biogenesis under both normal and diseased cellular conditions. The low-complexity (LC) domain of hnRNPs can become liquid-like droplets or reversible amyloid-like polymers by phase separation. Yet, whether phase separation of the LC domains contributes to physiological functions of hnRNPs remains unclear. hnRNPH1 contains two LC domains, LC1 and LC2. Here, we show that reversible phase separation of the LC1 domain is critical for both interaction with different kinds of RNA-binding proteins and control of the alternative-splicing activity of hnRNPH1. Interestingly, although not required for phase separation, the LC2 domain contributes to the robust transcriptional activation of hnRNPH1 when fused to the DNA-binding domain, as found recently in acute lymphoblastic leukemia. Our data suggest that the ability of the LC1 domain to phase-separate into reversible polymers or liquid-like droplets is essential for function of hnRNPH1 as an alternative RNA-splicing regulator, whereas the LC2 domain may contribute to the aberrant transcriptional activity responsible for cancer transformation.

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