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RNA Interference Pathways
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RNA Interference Pathways

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "RNA".

Deadline for manuscript submissions: 15 April 2025 | Viewed by 18720

Special Issue Editor

Dr. Tamas Orban

E-Mail Website
Guest Editor
Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Hungary
Interests: RNAi; RNA decay; miRNA; siRNA; DNA transposons

Special Issue Information

Dear Colleagues,

Based on unexpected scientific discoveries of the 20th century, where the color of petunias was changed through the “unusual” small-RNA-mediated regulation of worm development and mRNA degradation, RNA interference (RNAi) has been recognized as having a wide variety of regulatory pathways. The common effectors in these pathways are specific ribonucleoprotein complexes containing short, single-stranded RNA molecules, and members of the Argonaute protein family. At least three major pathways are considered to be RNAi-related: the short interfering RNA (siRNA) pathway, representing a molecular immune system against invasive genetic elements; the microRNA (miRNA) pathway, which evolved to be a complex, posttranscriptional regulatory network in eukaryotes; and the Piwi-associated RNA (piRNA) pathway, which was originally described as a defense system against transposable elements, particularly in germline cells.

Since the initial discovery of RNAi, and the Nobel Prize recognizing the scientific significance of RNAi in 2006, various aspects of the pathways have been intensively investigated. It was revealed that, besides the canonical maturation steps of the small RNAs and the related ribonucleoprotein complexes, several alternative biochemical routes also exist, indicating the evolutionary diversity of common regulatory networks. In addition to maturation complexities, the originally described functions have also been widened: the most prominent example is that, in addition to the initially discovered posttranscriptional silencing effects, RNAi has been shown to play important roles in transcriptional regulation and chromatin remodeling. At present, gene therapy applications are also considering RNAi-based methods, although understanding the molecular details of these pathways clearly reaches beyond pure scientific interest.

The aim of this Special Issue is to provide up-to-date knowledge on various aspects of RNA interference. Papers describing the new molecular aspects and functional diversity of these small RNA pathways are all welcome, as well as studies presenting the medical relevance or the therapeutic applications of siRNAs and miRNAs. Gathering the most recent results, using cutting-edge technologies in several model systems, we would like to show how diverse these pathways have become since the last common eukaryotic ancestor, and how modern molecular genetics, as well as molecular medicine, can benefit from this knowledge.

Dr. Tamas Orban
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • RNAi
  • silencing
  • siRNA
  • miRNA
  • piRNA
  • RISC
  • mRNA decay

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Published Papers (7 papers)

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Research

Jump to: Review

13 pages, 1962 KiB  
Article
miRBind: A Deep Learning Method for miRNA Binding Classification
by Eva Klimentová, Václav Hejret, Ján Krčmář, Katarína Grešová, Ilektra-Chara Giassa and Panagiotis Alexiou
Genes 2022, 13(12), 2323; https://doi.org/10.3390/genes13122323 - 9 Dec 2022
Cited by 4 | Viewed by 3602
Abstract
The binding of microRNAs (miRNAs) to their target sites is a complex process, mediated by the Argonaute (Ago) family of proteins. The prediction of miRNA:target site binding is an important first step for any miRNA target prediction algorithm. To date, the potential for [...] Read more.
The binding of microRNAs (miRNAs) to their target sites is a complex process, mediated by the Argonaute (Ago) family of proteins. The prediction of miRNA:target site binding is an important first step for any miRNA target prediction algorithm. To date, the potential for miRNA:target site binding is evaluated using either co-folding free energy measures or heuristic approaches, based on the identification of binding ‘seeds’, i.e., continuous stretches of binding corresponding to specific parts of the miRNA. The limitations of both these families of methods have produced generations of miRNA target prediction algorithms that are primarily focused on ‘canonical’ seed targets, even though unbiased experimental methods have shown that only approximately half of in vivo miRNA targets are ‘canonical’. Herein, we present miRBind, a deep learning method and web server that can be used to accurately predict the potential of miRNA:target site binding. We trained our method using seed-agnostic experimental data and show that our method outperforms both seed-based approaches and co-fold free energy approaches. The full code for the development of miRBind and a freely accessible web server are freely available. Full article
(This article belongs to the Special Issue RNA Interference Pathways)
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14 pages, 2717 KiB  
Article
Partial Disturbance of Microprocessor Function in Human Stem Cells Carrying a Heterozygous Mutation in the DGCR8 Gene
by Dóra Reé, Ábel Fóthi, Nóra Varga, Orsolya Kolacsek, Tamás I. Orbán and Ágota Apáti
Genes 2022, 13(11), 1925; https://doi.org/10.3390/genes13111925 - 23 Oct 2022
Viewed by 1938
Abstract
Maturation of microRNAs (miRNAs) begins by the “Microprocessor” complex, containing the Drosha endonuclease and its partner protein, "DiGeorge Syndrome Critical Region 8" (DGCR8). Although the main function of the two proteins is to coordinate the first step of precursor miRNAs formation, several studies [...] Read more.
Maturation of microRNAs (miRNAs) begins by the “Microprocessor” complex, containing the Drosha endonuclease and its partner protein, "DiGeorge Syndrome Critical Region 8" (DGCR8). Although the main function of the two proteins is to coordinate the first step of precursor miRNAs formation, several studies revealed their miRNA-independent functions in other RNA-related pathways (e.g., in snoRNA decay) or, for the DGCR8, the role in tissue development. To investigate the specific roles of DGCR8 in various cellular pathways, we previously established a human embryonic stem-cell (hESC) line carrying a monoallelic DGCR8 mutation by using the CRISPR-Cas9 system. In this study, we genetically characterized single-cell originated progenies of the cell line and showed that DGCR8 heterozygous mutation results in only a modest effect on the mRNA level but a significant decrease at the protein level. Self-renewal and trilineage differentiation capacity of these hESCs were not affected by the mutation. However, partial disturbance of the Microprocessor function could be revealed in pri-miRNA processing along the human chromosome 19 miRNA cluster in several clones. With all these studies, we can demonstrate that the mutant hESC line is a good model to study not only miRNA-related but also other “noncanonical” functions of the DGCR8 protein. Full article
(This article belongs to the Special Issue RNA Interference Pathways)
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16 pages, 5856 KiB  
Article
Effect of miR-302b MicroRNA Inhibition on Chicken Primordial Germ Cell Proliferation and Apoptosis Rate
by Bence Lázár, Nikolett Tokodyné Szabadi, Mahek Anand, Roland Tóth, András Ecker, Martin Urbán, Maria Teresa Salinas Aponte, Ganna Stepanova, Zoltán Hegyi, László Homolya, Eszter Patakiné Várkonyi, Bertrand Pain and Elen Gócza
Genes 2022, 13(1), 82; https://doi.org/10.3390/genes13010082 - 28 Dec 2021
Cited by 6 | Viewed by 2737
Abstract
The primordial germ cells (PGCs) are the precursors for both the oocytes and spermatogonia. Recently, a novel culture system was established for chicken PGCs, isolated from embryonic blood. The possibility of PGC long-term cultivation issues a new advance in germ cell preservation, biotechnology, [...] Read more.
The primordial germ cells (PGCs) are the precursors for both the oocytes and spermatogonia. Recently, a novel culture system was established for chicken PGCs, isolated from embryonic blood. The possibility of PGC long-term cultivation issues a new advance in germ cell preservation, biotechnology, and cell biology. We investigated the consequence of gga-miR-302b-5P (5P), gga-miR-302b-3P (3P) and dual inhibition (5P/3P) in two male and two female chicken PGC lines. In treated and control cell cultures, the cell number was calculated every four hours for three days by the XLS Imaging system. Comparing the cell number of control and treated lines on the first day, we found that male lines had a higher proliferation rate independently from the treatments. Compared to the untreated ones, the proliferation rate and the number of apoptotic cells were considerably reduced at gga-miR-302b-5P inhibition in all PGC lines on the third day of the cultivation. The control PGC lines showed a significantly higher proliferation rate than 3P inhibited lines on Day 3 in all PGC lines. Dual inhibition of gga-miR-302b mature miRNAs caused a slight reduction in proliferation rate, but the number of apoptotic cells increased dramatically. The information gathered by examining the factors affecting cell proliferation of PGCs can lead to new data in stem cell biology. Full article
(This article belongs to the Special Issue RNA Interference Pathways)
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14 pages, 2141 KiB  
Article
Posttranscriptional Regulation of the Human ABCG2 Multidrug Transporter Protein by Artificial Mirtrons
by Anita Schamberger, György Várady, Ábel Fóthi and Tamás I. Orbán
Genes 2021, 12(7), 1068; https://doi.org/10.3390/genes12071068 - 13 Jul 2021
Cited by 3 | Viewed by 2141
Abstract
ABCG2 is a membrane transporter protein that has been associated with multidrug resistance phenotype and tumor development. Additionally, it is expressed in various stem cells, providing cellular protection against endobiotics and xenobiotics. In this study, we designed artificial mirtrons to regulate ABCG2 expression [...] Read more.
ABCG2 is a membrane transporter protein that has been associated with multidrug resistance phenotype and tumor development. Additionally, it is expressed in various stem cells, providing cellular protection against endobiotics and xenobiotics. In this study, we designed artificial mirtrons to regulate ABCG2 expression posttranscriptionally. Applying EGFP as a host gene, we could achieve efficient silencing not only in luciferase reporter systems but also at the ABCG2 protein level. Moreover, we observed important new sequential-functional features of the designed mirtrons. Mismatch at the first position of the mirtron-derived small RNA resulted in better silencing than full complementarity, while the investigated middle and 3′ mismatches did not enhance silencing. These latter small RNAs operated most probably via non-seed specific translational inhibition in luciferase assays. Additionally, we found that a mismatch in the first position has not, but a second mismatch in the third position has abolished target mRNA decay. Besides, one nucleotide mismatch in the seed region did not impair efficient silencing at the protein level, providing the possibility to silence targets carrying single nucleotide polymorphisms or mutations. Taken together, we believe that apart from establishing an efficient ABCG2 silencing system, our designing pipeline and results on sequential-functional features are beneficial for developing artificial mirtrons for other targets. Full article
(This article belongs to the Special Issue RNA Interference Pathways)
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11 pages, 1419 KiB  
Article
CRISPR-Induced Expression of N-Terminally Truncated Dicer in Mouse Cells
by Radek Malik and Petr Svoboda
Genes 2021, 12(4), 540; https://doi.org/10.3390/genes12040540 - 8 Apr 2021
Viewed by 2514
Abstract
RNA interference (RNAi) designates sequence-specific mRNA degradation mediated by small RNAs generated from long double-stranded RNA (dsRNA) by RNase III Dicer. RNAi appears inactive in mammalian cells except for mouse oocytes, where high RNAi activity exists because of an N-terminally truncated Dicer isoform, [...] Read more.
RNA interference (RNAi) designates sequence-specific mRNA degradation mediated by small RNAs generated from long double-stranded RNA (dsRNA) by RNase III Dicer. RNAi appears inactive in mammalian cells except for mouse oocytes, where high RNAi activity exists because of an N-terminally truncated Dicer isoform, denoted DicerO. DicerO processes dsRNA into small RNAs more efficiently than the full-length Dicer expressed in somatic cells. DicerO is expressed from an oocyte-specific promoter of retrotransposon origin, which is silenced in other cell types. In this work, we evaluated CRISPR-based strategies for epigenetic targeting of the endogenous Dicer gene to restore DicerO expression and, consequently, RNAi. We show that reactivation of DicerO expression can be achieved in mouse embryonic stem cells, but it is not sufficient to establish a robust canonical RNAi response. Full article
(This article belongs to the Special Issue RNA Interference Pathways)
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Review

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20 pages, 2349 KiB  
Review
Pluripotency-Associated microRNAs in Early Vertebrate Embryos and Stem Cells
by Pouneh Maraghechi, Maria Teresa Salinas Aponte, András Ecker, Bence Lázár, Roland Tóth, Nikolett Tokodyné Szabadi and Elen Gócza
Genes 2023, 14(7), 1434; https://doi.org/10.3390/genes14071434 - 12 Jul 2023
Cited by 1 | Viewed by 1825
Abstract
MicroRNAs (miRNAs), small non-coding RNA molecules, regulate a wide range of critical biological processes, such as proliferation, cell cycle progression, differentiation, survival, and apoptosis, in many cell types. The regulatory functions of miRNAs in embryogenesis and stem cell properties have been extensively investigated [...] Read more.
MicroRNAs (miRNAs), small non-coding RNA molecules, regulate a wide range of critical biological processes, such as proliferation, cell cycle progression, differentiation, survival, and apoptosis, in many cell types. The regulatory functions of miRNAs in embryogenesis and stem cell properties have been extensively investigated since the early years of miRNA discovery. In this review, we will compare and discuss the impact of stem-cell-specific miRNA clusters on the maintenance and regulation of early embryonic development, pluripotency, and self-renewal of embryonic stem cells, particularly in vertebrates. Full article
(This article belongs to the Special Issue RNA Interference Pathways)
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24 pages, 1229 KiB  
Review
Essential Role of the 14q32 Encoded miRNAs in Endocrine Tumors
by Lilla Krokker, Attila Patócs and Henriett Butz
Genes 2021, 12(5), 698; https://doi.org/10.3390/genes12050698 - 8 May 2021
Cited by 9 | Viewed by 3501
Abstract
Background: The 14q32 cluster is among the largest polycistronic miRNA clusters. miRNAs encoded here have been implicated in tumorigenesis of multiple organs including endocrine glands. Methods: Critical review of miRNA studies performed in endocrine tumors have been performed. The potential relevance of 14q32 [...] Read more.
Background: The 14q32 cluster is among the largest polycistronic miRNA clusters. miRNAs encoded here have been implicated in tumorigenesis of multiple organs including endocrine glands. Methods: Critical review of miRNA studies performed in endocrine tumors have been performed. The potential relevance of 14q32 miRNAs through investigating their targets, and integrating the knowledge provided by literature data and bioinformatics predictions have been indicated. Results: Pituitary adenoma, papillary thyroid cancer and a particular subset of pheochromocytoma and adrenocortical cancer are characterized by the downregulation of miRNAs encoded by the 14q32 cluster. Pancreas neuroendocrine tumors, most of the adrenocortical cancer and medullary thyroid cancer are particularly distinct, as 14q32 miRNAs were overexpressed. In pheochromocytoma and growth-hormone producing pituitary adenoma, however, both increased and decreased expression of 14q32 miRNAs cluster members were observed. In the background of this phenomenon methodological, technical and biological factors are hypothesized and discussed. The functions of 14q32 miRNAs were also revealed by bioinformatics and literature data mining. Conclusions: 14q32 miRNAs have a significant role in the tumorigenesis of endocrine organs. Regarding their stable expression in the circulation of healthy individuals, further investigation of 14q32 miRNAs could provide a potential for use as biomarkers (diagnostic or prognostic) in endocrine neoplasms. Full article
(This article belongs to the Special Issue RNA Interference Pathways)
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