scholarly journals SINEUPs: a novel toolbox for RNA therapeutics

2021 ◽  
Author(s):  
Stefano Espinoza ◽  
Carlotta Bon ◽  
Paola Valentini ◽  
Bianca Pierattini ◽  
Abraham Tettey Matey ◽  
...  
Keyword(s):  
Mrna Translation ◽  
Functional Class ◽  
Structural Domains ◽  
Protein Coding ◽  
Rna Molecules ◽  
New Class ◽  
Endogenous Protein ◽  
Antisense Region ◽  
Antisense Lncrnas ◽  
Druggable Targets

Abstract RNA molecules have emerged as a new class of promising therapeutics to expand the range of druggable targets in the genome. In addition to ‘canonical’ protein-coding mRNAs, the emerging richness of sense and antisense long non-coding RNAs (lncRNAs) provides a new reservoir of molecular tools for RNA-based drugs. LncRNAs are composed of modular structural domains with specific activities involving the recruitment of protein cofactors or directly interacting with nucleic acids. A single therapeutic RNA transcript can then be assembled combining domains with defined secondary structures and functions, and antisense sequences specific for the RNA/DNA target of interest. As the first representative molecules of this new pharmacology, we have identified SINEUPs, a new functional class of natural antisense lncRNAs that increase the translation of partially overlapping mRNAs. Their activity is based on the combination of two domains: an embedded mouse inverted SINEB2 element that enhances mRNA translation (effector domain) and an overlapping antisense region that provides specificity for the target sense transcript (binding domain). By genetic engineering, synthetic SINEUPs can potentially target any mRNA of interest increasing translation and therefore the endogenous level of the encoded protein. In this review, we describe the state-of-the-art knowledge of SINEUPs and discuss recent publications showing their potential application in diseases where a physiological increase of endogenous protein expression can be therapeutic.

scholarly journals Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase

2021 ◽  
Vol 12 ◽  
Author(s):  
Giulia Zarantonello ◽  
Michele Arnoldi ◽  
Michele Filosi ◽  
Toma Tebaldi ◽  
Giovanni Spirito ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neuronal Development ◽  
Autism Spectrum ◽  
Protein Coding ◽  
Additional Layer ◽  
Antisense Region ◽  
Antisense Lncrnas ◽  
Spectrum Disorders ◽  
Rna Domains

CHD8 represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to CHD8 haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complaints. While extensive studies have been conducted on the possible consequences of CHD8 suppression and protein coding RNAs dysregulation during neuronal development, the effects of transcriptional changes of long non-coding RNAs (lncRNAs) remain unclear. In this study, we focused on a peculiar class of natural antisense lncRNAs, SINEUPs, that enhance translation of a target mRNA through the activity of two RNA domains, an embedded transposable element sequence and an antisense region. By looking at dysregulated transcripts following CHD8 knock down (KD), we first identified RAB11B-AS1 as a potential SINEUP RNA for its domain configuration. Then we demonstrated that such lncRNA is able to increase endogenous RAB11B protein amounts without affecting its transcriptional levels. RAB11B has a pivotal role in vesicular trafficking, and mutations on this gene correlate with intellectual disability and microcephaly. Thus, our study discloses an additional layer of molecular regulation which is altered by CHD8 suppression. This represents the first experimental confirmation that naturally occurring SINEUP could be involved in ASD pathogenesis and underscores the importance of dysregulation of functional lncRNAs in neurodevelopment.

scholarly journals Effects on protein synthesis of injecting synthetic polyribonucleotides into living cells

1974 ◽  
Vol 144 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Hugh Woodland ◽  
Sarah E. Ayers
Keyword(s):  
Protein Synthesis ◽  
Xenopus Laevis ◽  
Potent Inhibitor ◽  
Living Cells ◽  
Initiation Factor ◽  
Rna Molecules ◽  
Endogenous Protein ◽  
Limited Supply ◽  
Inhibitor Of Protein Synthesis ◽  
Haemoglobin Synthesis

Micro-injection into the oocytes and eggs of Xenopus laevis was used to ascertain the effects of synthetic polyribonucleotides on protein synthesis in living cells. Poly(U) and poly(A) were not translated detectably, nor did they change the rate of endogenous protein synthesis. The same was true of poly(G,U), poly(A,G,U), poly(A,C,G,U), G-U-G-(U)n, A-(U)n and AUG. In contrast, A-U-G-(U)n was a potent inhibitor of protein synthesis in the cell. This might be because it is initiated normally but lacks a termination codon, or because it inhibits the translation of other molecules in some way not dependent on its normal initiation. Poly(G,U), poly(A,G,U) and poly(A,C,G,U) inhibited haemoglobin synthesis when they were injected into the oocyte with haemoglobin mRNA. The synthetic polyribonucleotides did not inhibit the translation of the natural mRNA when the two sorts of molecules were injected at different times. It is suggested that the synthetic RNA molecules compete with the natural mRNA for a pre-initiation factor in limited supply.

Dual Isoform Sequencing Reveals a Multifaceted Transcriptional Architecture of a Prototype Baculovirus

2021 ◽  
Author(s):  
Gábor Torma ◽  
Dóra Tombácz ◽  
Norbert Moldován ◽  
Ádám Fülöp ◽  
István Prazsák ◽  
...  
Keyword(s):  
Protein Coding ◽  
Rna Molecules ◽  
Non Coding Rna ◽  
Oxford Nanopore ◽  
The Pacific ◽  
Viral Genes ◽  
Long Read ◽  
Oxford Nanopore Technologies ◽  
Overlapping Transcripts

Abstract In this study, we used two long-read sequencing (LRS) techniques, Sequel from the Pacific Biosciences and MinION from Oxford Nanopore Technologies, for the transcriptional characterization of a prototype baculovirus, Autographacalifornica multiple nucleopolyhedrovirus. LRS is able to read full-length RNA molecules, and thereby to distinguish between transcript isoforms, mono- and polycistronic RNAs, and overlapping transcripts. Altogether, we detected 875 transcripts, of which 759 are novel and 116 have been annotated previously. These RNA molecules include 41 novel putative protein coding transcript (each containing 5’-truncated in-frame ORFs), 14 monocistronic transcripts, 99 multicistronic RNAs, 101 non-coding RNA, and 504 length isoforms. We also detected RNA methylation in 12 viral genes and RNA hyper-editing in the longer 5’-UTR transcript isoform of ORF 19 gene.

Bioinformatics Methods for Studying MicroRNA and ARE-Mediated Regulation of Post-Transcriptional Gene Expression

2010 ◽  
Vol 1 (3) ◽  
pp. 97-112 ◽  
Author(s):  
Richipal Singh Bindra ◽  
Jason T. L. Wang ◽  
Paramjeet Singh Bagga
Keyword(s):  
Mirna Target ◽  
Target Prediction ◽  
Untranslated Regions ◽  
Regulatory Rna ◽  
Rna Motifs ◽  
Protein Coding ◽  
Rna Molecules ◽  
Cellular Processes ◽  
Target Sites ◽  
Transcriptional Gene Regulation

MicroRNAs (miRNAs) are short single-stranded RNA molecules with 21-22 nucleotides known to regulate post-transcriptional expression of protein-coding genes involved in most of the cellular processes. Prediction of miRNA targets is a challenging bioinformatics problem. AU-rich elements (AREs) are regulatory RNA motifs found in the 3’ untranslated regions (UTRs) of mRNAs, and they play dominant roles in the regulated decay of short-lived human mRNAs via specific interactions with proteins. In this paper, the authors review several miRNA target prediction tools and data sources, as well as computational methods used for the prediction of AREs. The authors discuss the connection between miRNA and ARE-mediated post-transcriptional gene regulation. Finally, a data mining method for identifying the co-occurrences of miRNA target sites in ARE containing genes is presented.

scholarly journals A health disparities study of MicroRNA-146a expression in prostate cancer samples derived from African American and European American patients

2020 ◽  
Vol 10 (2) ◽  
pp. 1
Author(s):  
Monet Stevenson ◽  
Narendra Narendra Banerjee ◽  
Narendra Banerjee ◽  
Kuldeep Rawat ◽  
Lin Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
Association Studies ◽  
Single Gene ◽  
Micro Rna ◽  
Genome Wide Association Studies ◽  
Racial Groups ◽  
Protein Coding ◽  
Rna Molecules ◽  
Prostate Carcinogenesis

Considering the prevalence of prostate cancer all over the world, it is desired to have tools, technologies, and biomarkers which help in early detection of the disease and discriminate different races and ethnic groups. Genetic information from the single gene analysis and genome-wide association studies have identified few biomarkers, however, the drivers of prostate cancer remain unknown in the majority of prostate cancer patients. In those cases where genetic association has been identified, the genes confer only a modest risk of this cancer, hence, making them less relevant for risk counseling and disease management. There is a need for additional biomarkers for diagnosis and prognosis of prostate cancer. MicroRNAs are a class of non-protein coding RNA molecules that are frequently dysregulated in different cancers including prostate cancer and show promise as diagnostic biomarkers and targets for therapy. Here we describe the role of micro RNA 146a (miR-146a) which may serve as a diagnostic and prognostic marker for prostate cancer, as indicated from the data presented in this report. Also, a pilot study indicated differential expression of miR-146a in prostate cancer cell lines and tissues from different racial groups. Reduced expression of miR-146a was observed in African American tumor tissues compared to those from European Whites This report provides a novel insight into understanding the prostate carcinogenesis.

scholarly journals Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer

2020 ◽  
Vol 6 (3) ◽  
pp. 27 ◽  
Author(s):  
Dominik A. Barth ◽  
Felix Prinz ◽  
Julia Teppan ◽  
Katharina Jonas ◽  
Christiane Klec ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Protein Coding ◽  
Rna Molecules ◽  
Von Hippel Lindau ◽  
Hypoxic Conditions ◽  
Main Regulator ◽  
Upstream Regulators

Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.

scholarly journals MicroRNAs: regulators of gene expression and cell differentiation

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3646-3653 ◽  
Author(s):  
Ramesh A. Shivdasani
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Protein Translation ◽  
Specific Aspect ◽  
Mirna Biogenesis ◽  
Mirna Regulation ◽  
Protein Coding ◽  
Rna Molecules ◽  
Protein Levels ◽  
Micro Rnas

AbstractThe existence and roles of a class of abundant regulatory RNA molecules have recently come into sharp focus. Micro-RNAs (miRNAs) are small (approximately 22 bases), non–protein-coding RNAs that recognize target sequences of imperfect complementarity in cognate mRNAs and either destabilize them or inhibit protein translation. Although mechanisms of miRNA biogenesis have been elucidated in some detail, there is limited appreciation of their biological functions. Reported examples typically focus on miRNA regulation of a single tissue-restricted transcript, often one encoding a transcription factor, that controls a specific aspect of development, cell differentiation, or physiology. However, computational algorithms predict up to hundreds of putative targets for individual miRNAs, single transcripts may be regulated by multiple miRNAs, and miRNAs may either eliminate target gene expression or serve to finetune transcript and protein levels. Theoretical considerations and early experimental results hence suggest diverse roles for miRNAs as a class. One appealing possibility, that miRNAs eliminate low-level expression of unwanted genes and hence refine unilineage gene expression, may be especially amenable to evaluation in models of hematopoiesis. This review summarizes current understanding of miRNA mechanisms, outlines some of the important outstanding questions, and describes studies that attempt to define miRNA functions in hematopoiesis.

scholarly journals Codon usage is an important determinant of gene expression levels largely through its effects on transcription

2016 ◽  
Vol 113 (41) ◽  
pp. E6117-E6125 ◽  
Author(s):  
Zhipeng Zhou ◽  
Yunkun Dang ◽  
Mian Zhou ◽  
Lin Li ◽  
Chien-hung Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Codon Usage ◽  
Important Determinant ◽  
Mrna Translation ◽  
Mrna Levels ◽  
Protein Coding ◽  
Expression Levels ◽  
Highly Expressed Genes ◽  
The Impact ◽  
Gene Expression Levels

Codon usage biases are found in all eukaryotic and prokaryotic genomes, and preferred codons are more frequently used in highly expressed genes. The effects of codon usage on gene expression were previously thought to be mainly mediated by its impacts on translation. Here, we show that codon usage strongly correlates with both protein and mRNA levels genome-wide in the filamentous fungus Neurospora. Gene codon optimization also results in strong up-regulation of protein and RNA levels, suggesting that codon usage is an important determinant of gene expression. Surprisingly, we found that the impact of codon usage on gene expression results mainly from effects on transcription and is largely independent of mRNA translation and mRNA stability. Furthermore, we show that histone H3 lysine 9 trimethylation is one of the mechanisms responsible for the codon usage-mediated transcriptional silencing of some genes with nonoptimal codons. Together, these results uncovered an unexpected important role of codon usage in ORF sequences in determining transcription levels and suggest that codon biases are an adaptation of protein coding sequences to both transcription and translation machineries. Therefore, synonymous codons not only specify protein sequences and translation dynamics, but also help determine gene expression levels.

scholarly journals Functions and Roles of Long-Non-Coding RNAs in Human Nasopharyngeal Carcinoma

2018 ◽  
Vol 45 (3) ◽  
pp. 1191-1204 ◽  
Author(s):  
JingJing Wu ◽  
Swei Sunny Hann
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Functional Characterization ◽  
Clinical Information ◽  
Stem Cell Differentiation ◽  
Cancer Prognosis ◽  
Protein Coding ◽  
Rna Molecules ◽  
Gene Therapies ◽  
Non Coding Rnas

Nasopharyngeal carcinoma (NPC) is one of the most common cancers originating in the nasopharynx and occurring at high frequency in South-eastern Asia and North Africa. Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNA molecules and key regulators of developmental, physiological, and pathological processes in humans. Emerging studies have shown that lncRNAs play critical roles in tumorgenicity and cancer prognosis. With the development of deep sequencing analyses, an extensive amount of functional lncRNAs have been discovered in nasopharyngeal carcinoma tissues and cell lines. However, the roles and mechanisms of aberrantly expressed lncRNAs in the pathogenesis of NPC are not fully understood. In this review, we briefly illustrate the concept, identification, functional characterization, and summarize recent advancements of biological functions of lncRNAs with heterogeneous mechanistic characterization and their involvement in NPC. Then, we describe individual lncRNAs that have been associated with tumorgenesis, growth, invasion, cancer stem cell differentiation, metastasis, drug resistance and discuss the strategies of their therapeutic manipulation in NPC. We also review the emerging insights into the role of lncRNAs and their potential as biomarkers and therapeutic targets for novel treatment paradigms. Finally, we highlight the up-to-date of clinical information involving lncRNAs and future directions in the linking lncRNAs to potential gene therapies, and how modifications of lncRNAs can be exploited for prevention and treatment of NPC.

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