Synthetic long non-coding RNAs [SINEUPs] rescue defective gene expression in vivo

Heart failure comprises of clinically distinct inciting causes but a consistent pattern of change in myocardial gene expression supports the hypothesis that unifying biochemical mechanisms underlie disease progression. The recent RNA-seq revolution has enabled whole transcriptome profiling, using deep-sequencing technologies. Up to 70% of the genome is now known to be transcribed into RNA, a significant proportion of which is long non-coding RNAs (lncRNAs), defined as polyribonucleotides of ≥200 nucleotides. This project aims to discover whether the myocardium expression of lncRNAs changes in the failing heart. Paired end RNA-seq from a 300-400bp library of ‘stretched’ mouse myocyte total RNA was carried out to generate 76-mer sequence reads. Mechanically stretching myocytes with equibiaxial stretch apparatus mimics pathological hypertrophy in the heart. Transcripts were assembled and aligned to reference genome mm9 (UCSC), abundance determined and differential expression of novel transcripts and alternative splice variants were compared with that of control (non-stretched) mouse myocytes. Five novel transcripts have been identified in our RNA-seq that are differentially expressed in stretched myocytes compared with non-stretched. These are regions of the genome that are currently unannotated and potentially are transcribed into non-coding RNAs. Roles of known lncRNAs include control of gene expression, either by direct interaction with complementary regions of the genome or association with chromatin remodelling complexes which act on the epigenome.Changes in expression of genes which contribute to the deterioration of the failing heart could be due to the actions of these novel lncRNAs, immediately suggesting a target for new pharmaceuticals. Changes in the expression of these novel transcripts will be validated in a larger sample size of stretched myocytes vs non-stretched myocytes as well as in the hearts of transverse aortic constriction (TAC) mice vs Sham (surgical procedure without the aortic banding). In vivo investigations will then be carried out, using siLNA antisense technology to silence novel lncRNAs in mice.

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Targeting of microRNAs for therapeutics

Biochemical Society Transactions ◽

10.1042/bst0361197 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1197-1200 ◽

Cited By ~ 38

Author(s):

Jan Stenvang ◽

Morten Lindow ◽

Sakari Kauppinen

Keyword(s):

Gene Expression ◽

Cardiovascular Diseases ◽

High Stability ◽

Viral Infections ◽

Modified Oligonucleotides ◽

Rna Molecules ◽

Locked Nucleic Acids ◽

Non Coding Rnas ◽

High Binding Affinity

miRNAs (microRNAs) comprise a class of small endogenous non-coding RNAs that post-transcriptionally repress gene expression by base-pairing with their target mRNAs. Recent evidence has shown that miRNAs play important roles in a wide variety of human diseases, such as viral infections, cancer and cardiovascular diseases, and thus miRNAs have rapidly emerged as potential targets for therapeutics. LNAs (locked nucleic acids) comprise a class of bicyclic conformational analogues of RNA, which exhibit high binding affinity to complementary RNA molecules and high stability in blood and tissues in vivo. Recent reports on LNA-mediated miRNA silencing in rodents and primates support the potential of LNA-modified oligonucleotides in studying miRNA functions in vivo and in the future development of miRNA-based therapeutics.

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The Non-coding MicroRNA-223 is a Promising Biomarker of Chronic Kidney Disease

EMJ Nephrology ◽

10.33590/emjnephrol/21-00057 ◽

2021 ◽

pp. 91-95

Author(s):

Valerie Metzinger-Le Meuth ◽

Laurent Metzinger

Keyword(s):

Gene Expression ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Diseases ◽

Mirna Regulation ◽

Mrna Targets ◽

Cardiovascular Damage ◽

Non Coding Rnas ◽

Post Transcriptional Regulation

Renal diseases are consecutive to a deregulation of gene expression regulated by non-coding RNAs. These non-coding RNAs were discovered at the turn of the 21st century when it was established that post-transcriptional regulation was performed through small non-coding RNAs, known as microRNAs (miRNAs). Up to 3,000 miRNAs are expressed by human cells. They are small, single-stranded nucleic acids, which trigger translational repression of mRNA by base-pairing with the 3′ untranslated region of their mRNA targets. In addition to miRNA regulation, it was also demonstrated that 60,000 long non-coding RNAs are expressed in the human cell and that they are able to regulate gene expression at all levels. The roles of these various RNA families are just beginning to be understood in the field of nephrology. In the past decade, the authors and various others have published that several miRNAs are deregulated during the onset of chronic kidney disease (CKD) and are associated with cardiovascular damage. This review focuses on miRNA-223 (miR-223) as its expression is increased in vivo in the large vessels of a mouse model of CKD, whereas it is diminished in the serum of both mice and human patients with CKD. In patients, miR-223 expression was correlated with all-cause mortality, as well as cardiovascular and renal events. Molecular clues were given by a multi-omics approach, indicating that miR-223 modulates gene regulation at all levels including mRNA expression, protein amounts, and metabolic molecule accumulation. miR-223 is thus a potential target to prevent or treat complications of CKD pathogenesis.

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MicroRNA regulation of vascular function

Vascular Biology ◽

10.1530/vb-19-0009 ◽

2019 ◽

Vol 1 (1) ◽

pp. H41-H46

Author(s):

David Mellis ◽

Andrea Caporali

Keyword(s):

Gene Expression ◽

Therapeutic Intervention ◽

Vascular Function ◽

State Of The Art ◽

Genetic Networks ◽

Mirna Biogenesis ◽

Technical Feasibility ◽

Microrna Regulation ◽

Non Coding Rnas

MicroRNAs (miRNAs) are small non-coding RNAs that orchestrate genetic networks by modulating gene expression. Given their importance in vascular development, homeostasis and diseases, along with the technical feasibility in deploying their function in vivo, the so-called ‘vascular miRNAs’ have become key targets for therapeutic intervention. Herein, we have summarised the state-of-the-art on vascular miRNAs and we have discussed the role miRNA biogenesis and the extracellular vesicles (EVs) miRNA transport in vascular biology.

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Insights into the Functions of LncRNAs in Drosophila

International Journal of Molecular Sciences ◽

10.3390/ijms20184646 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4646 ◽

Cited By ~ 3

Author(s):

Keqin Li ◽

Yuanliangzi Tian ◽

Ya Yuan ◽

Xiaolan Fan ◽

Mingyao Yang ◽

...

Keyword(s):

Gene Expression ◽

Embryo Development ◽

Stress Resistance ◽

Expression Patterns ◽

In Vivo Studies ◽

Biological Processes ◽

Biological Functions ◽

Specific Expression ◽

Non Coding Rnas

Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs longer than 200 nucleotides (nt). LncRNAs have high spatiotemporal specificity, and secondary structures have been preserved throughout evolution. They have been implicated in a range of biological processes and diseases and are emerging as key regulators of gene expression at the epigenetic, transcriptional, and post-transcriptional levels. Comparative analyses of lncRNA functions among multiple organisms have suggested that some of their mechanisms seem to be conserved. Transcriptome studies have found that some Drosophila lncRNAs have highly specific expression patterns in embryos, nerves, and gonads. In vivo studies of lncRNAs have revealed that dysregulated expression of lncRNAs in Drosophila may result in impaired embryo development, impaired neurological and gonadal functions, and poor stress resistance. In this review, we summarize the epigenetic, transcriptional, and post-transcriptional mechanisms of lncRNAs and mainly focus on recent insights into the transcriptome studies and biological functions of lncRNAs in Drosophila.

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New Putative Long Non-Coding RNAs (lncRNA) Revealed by Pan-Transcriptome of the Emerging Human Pathogenic Fungus Talaromyces Marneffei

10.21203/rs.3.rs-1050608/v1 ◽

2021 ◽

Author(s):

David Aciole Barbosa ◽

Alexandre Santos Simeone ◽

Ana Carolina Humberto ◽

Yara Natercia Lima Faustino de Maria ◽

Regina Costa de Oliveira ◽

...

Keyword(s):

Gene Expression ◽

Transcriptome Assembly ◽

Pathogenic Fungus ◽

The Novel ◽

Talaromyces Marneffei ◽

Expression Control ◽

Gene Expression Control ◽

Human Pathogenic Fungus ◽

Non Coding Rnas

Abstract Previous genomic/transcriptomic analyses of Talaromyces marneffei (TM) unravelled relevant pathogenicity-related elements, as well as chromosomal regions potentially involved with the production of non-coding RNAs (ncRNAs), which have been parsimoniously reported in fungi. This manuscript describes a comprehensive pan-transcriptome assembly for TM that identifies a series of previously undetected genetic elements in this emerging pathogenic fungus. Our results confirm that ~58.28% of the 9,480 genes currently annotated in the TM genome are, in fact, transcribed in vivo and that ~23.6% of them may display alternative isomorphs. Moreover, we identified 585 transcripts that do not match any gene currently mapped in the genome, represented by 90 coding transcripts and 140 ncRNAs, including 48 long non-coding RNAs (lncRNAs). Overall, we expect that the novel elements described herein may contribute to improve the currently available Talaromyces databases and foster studies aiming at characterizing lncRNA-mediated gene expression control in fungi.

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The Causes and Consequences of miR-503 Dysregulation and Its Impact on Cardiovascular Disease and Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.629611 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yanjing He ◽

Yin Cai ◽

Pearl Mingchu Pai ◽

Xinling Ren ◽

Zhengyuan Xia

Keyword(s):

Gene Expression ◽

Cardiovascular Disease ◽

Diagnostic Marker ◽

Translational Repression ◽

Biological Processes ◽

Regulate Gene Expression ◽

Non Coding Rnas ◽

And Oxidative Stress

microRNAs (miRs) are short, non-coding RNAs that regulate gene expression by mRNA degradation or translational repression. Accumulated studies have demonstrated that miRs participate in various biological processes including cell differentiation, proliferation, apoptosis, metabolism and development, and the dysregulation of miRs expression are involved in different human diseases, such as neurological, cardiovascular disease and cancer. microRNA-503 (miR-503), one member of miR-16 family, has been studied widely in cardiovascular disease and cancer. In this review, we summarize and discuss the studies of miR-503 in vitro and in vivo, and how miR-503 regulates gene expression from different aspects of pathological processes of diseases, including carcinogenesis, angiogenesis, tissue fibrosis and oxidative stress; We will also discuss the mechanisms of dysregulation of miR-503, and whether miR-503 could be applied as a diagnostic marker or therapeutic target in cardiovascular disease or cancer.

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