International Journal of Molecular Sciences

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18 pages, 2785 KiB

Open AccessArticle

Human-Specific Regulation of Neurotrophic Factors MANF and CDNF by microRNAs

by Julia Konovalova, Dmytro Gerasymchuk, Sergio Navarette Arroyo, Sven Kluske, Francesca Mastroianni, Alba Vargas Pereyra and Andrii Domanskyi

Int. J. Mol. Sci. 2021, 22(18), 9691; https://doi.org/10.3390/ijms22189691 - 7 Sep 2021

Cited by 8 | Viewed by 3623

Abstract

Mesencephalic astrocyte derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are novel evolutionary conserved trophic factors, which exhibit cytoprotective activity via negative regulation of unfolded protein response (UPR) and inflammation. Despite multiple reports demonstrating detrimental effect of MANF/CDNF downregulation, little is [...] Read more.

Mesencephalic astrocyte derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are novel evolutionary conserved trophic factors, which exhibit cytoprotective activity via negative regulation of unfolded protein response (UPR) and inflammation. Despite multiple reports demonstrating detrimental effect of MANF/CDNF downregulation, little is known about the control of their expression. miRNAs—small non-coding RNAs—are important regulators of gene expression. Their dysregulation was demonstrated in multiple pathological processes and their ability to modulate levels of other neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was previously reported. Here, for the first time we demonstrated direct regulation of MANF and CDNF by miRNAs. Using bioinformatic tools, reporter assay and analysis of endogenous MANF and CDNF, we identified that miR-144 controls MANF expression, and miR-134 and miR-141 downregulate CDNF levels. We also demonstrated that this effect is human-specific and is executed via predicted binding sites of corresponding miRNAs. Finally, we found that miR-382 suppressed hCDNF expression indirectly. In conclusion, we demonstrate for the first time direct regulation of MANF and CDNF expression by specific miRNAs, despite the fact their binding sites are not strongly evolutionary conserved. Furthermore, we demonstrate a functional effect of miR-144 mediated regulation of MANF on ER stress response markers. These findings emphasize that (1) prediction of miRNA targets based on evolutionary conservation may miss biologically meaningful regulatory pairs; and (2) interpretation of miRNA regulatory effects in animal models should be cautiously validated. Full article

(This article belongs to the Special Issue microRNA Regulatory Network)

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15 pages, 10171 KiB

Open AccessArticle

Molecular Network Approach Reveals Rictor as a Central Target of Cardiac ProtectomiRs

by András Makkos, Bence Ágg, Zoltán V. Varga, Zoltán Giricz, Mariann Gyöngyösi, Dominika Lukovic, Rainer Schulz, Monika Barteková, Anikó Görbe and Péter Ferdinandy

Int. J. Mol. Sci. 2021, 22(17), 9539; https://doi.org/10.3390/ijms22179539 - 2 Sep 2021

Cited by 8 | Viewed by 2628

Abstract

Cardioprotective medications are still unmet clinical needs. We have previously identified several cardioprotective microRNAs (termed ProtectomiRs), the mRNA targets of which may reveal new drug targets for cardioprotection. Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with [...] Read more.

Cardioprotective medications are still unmet clinical needs. We have previously identified several cardioprotective microRNAs (termed ProtectomiRs), the mRNA targets of which may reveal new drug targets for cardioprotection. Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction (AMI). By using a network theoretical approach, we identified 882 potential target genes of 18 previously identified protectomiRs. The Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of AMI and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning. This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection. Full article

(This article belongs to the Special Issue microRNA Regulatory Network)

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13 pages, 3601 KiB

Open AccessArticle

Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

by Daniel Pérez-Cremades, Ana B. Paes, Xavier Vidal-Gómez, Ana Mompeón, Carlos Hermenegildo and Susana Novella

Int. J. Mol. Sci. 2021, 22(15), 8193; https://doi.org/10.3390/ijms22158193 - 30 Jul 2021

Viewed by 2238

Abstract

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory [...] Read more.

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA–transcription factor–downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells. Full article

(This article belongs to the Special Issue microRNA Regulatory Network)

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19 pages, 9388 KiB

Open AccessArticle

Multi–Omics Analysis of Key microRNA–mRNA Metabolic Regulatory Networks in Skeletal Muscle of Obese Rabbits

by Yanhong Li, Jie Wang, Mauricio A. Elzo, Mingchuan Gan, Tao Tang, Jiahao Shao, Tianfu Lai, Yuan Ma, Xianbo Jia and Songjia Lai

Int. J. Mol. Sci. 2021, 22(8), 4204; https://doi.org/10.3390/ijms22084204 - 19 Apr 2021

Cited by 10 | Viewed by 3083

Abstract

microRNAs (miRNAs), small non-coding RNA with a length of about 22 nucleotides, are involved in the energy metabolism of skeletal muscle cells. However, their molecular mechanism of metabolism in rabbit skeletal muscle is still unclear. In this study, 16 rabbits, 8 in the [...] Read more.

microRNAs (miRNAs), small non-coding RNA with a length of about 22 nucleotides, are involved in the energy metabolism of skeletal muscle cells. However, their molecular mechanism of metabolism in rabbit skeletal muscle is still unclear. In this study, 16 rabbits, 8 in the control group (CON–G) and 8 in the experimental group (HFD–G), were chosen to construct an obese model induced by a high–fat diet fed from 35 to 70 days of age. Subsequently, 54 differentially expressed miRNAs, 248 differentially expressed mRNAs, and 108 differentially expressed proteins related to the metabolism of skeletal muscle were detected and analyzed with three sequencing techniques (small RNA sequencing, transcriptome sequencing, and tandem mass tab (TMT) protein technology). It was found that 12 miRNAs and 12 core genes (e.g., CRYL1, VDAC3 and APIP) were significantly different in skeletal muscle from rabbits in the two groups. The network analysis showed that seven miRNA-mRNA pairs were involved in metabolism. Importantly, two miRNAs (miR-92a-3p and miR-30a/c/d-5p) regulated three transcription factors (MYBL2, STAT1 and IKZF1) that may be essential for lipid metabolism. These results enhance our understanding of molecular mechanisms associated with rabbit skeletal muscle metabolism and provide a basis for future studies in the metabolic diseases of human obesity. Full article

(This article belongs to the Special Issue microRNA Regulatory Network)

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27 pages, 4676 KiB

Open AccessArticle

Reciprocal Changes in miRNA Expression with Pigmentation and Decreased Proliferation Induced in Mouse B16F1 Melanoma Cells by l-Tyrosine and 5-Bromo-2′-Deoxyuridine

by Hernán Mauricio Rivera, Esther Natalia Muñoz, Daniel Osuna, Mauro Florez, Michael Carvajal and Luis Alberto Gómez

Int. J. Mol. Sci. 2021, 22(4), 1591; https://doi.org/10.3390/ijms22041591 - 5 Feb 2021

Cited by 4 | Viewed by 3098

Abstract

Background: Many microRNAs have been identified as critical mediators in the progression of melanoma through its regulation of genes involved in different cellular processes such as melanogenesis, cell cycle control, and senescence. However, microRNAs’ concurrent participation in syngeneic mouse B16F1 melanoma cells [...] Read more.

Background: Many microRNAs have been identified as critical mediators in the progression of melanoma through its regulation of genes involved in different cellular processes such as melanogenesis, cell cycle control, and senescence. However, microRNAs’ concurrent participation in syngeneic mouse B16F1 melanoma cells simultaneously induced decreased proliferation and differential pigmentation by exposure to 5-Brd-2′-dU (5’Bromo-2-deoxyuridine) and L-Tyr (L-Tyrosine) respectively, is poorly understood. Aim: To evaluate changes in the expression of microRNAs and identify which miRNAs in-network may contribute to the functional bases of phenotypes of differential pigmentation and reduction of proliferation in B16F1 melanoma cells exposed to 5-Brd-2′-dU and L-Tyr. Methods: Small RNAseq evaluation of the expression profiles of miRNAs in B16F1 melanoma cells exposed to 5-Brd-2′-dU (2.5 μg/mL) and L-Tyr (5 mM), as well as the expression by qRT-PCR of some molecular targets related to melanogenesis, cell cycle, and senescence. By bioinformatic analysis, we constructed network models of regulation and co-expression of microRNAs. Results: We confirmed that stimulation or repression of melanogenesis with L-Tyr or 5-Brd-2′-dU, respectively, generated changes in melanin concentration, reduction in proliferation, and changes in expression of microRNAs 470-3p, 470-5p, 30d-5p, 129-5p, 148b-3p, 27b-3p, and 211-5p, which presented patterns of coordinated and reciprocal co-expression, related to changes in melanogenesis through their putative targets Mitf, Tyr and Tyrp1, and control of cell cycle and senescence: Cyclin D1, Cdk2, Cdk4, p21, and p27. Conclusions: These findings provide insights into the molecular biology of melanoma of the way miRNAs are coordinated and reciprocal expression that may operate in a network as molecular bases for understanding changes in pigmentation and decreased proliferation induced in B16F1 melanoma cells exposed to L-Tyr and 5-Brd-2′-dU. Full article

(This article belongs to the Special Issue microRNA Regulatory Network)

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Review

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17 pages, 350 KiB

Open AccessReview

Non-Coding RNAs as Regulators of Myogenesis and Postexercise Muscle Regeneration

by Karolina Archacka, Maria A. Ciemerych, Anita Florkowska and Karolina Romanczuk

Int. J. Mol. Sci. 2021, 22(21), 11568; https://doi.org/10.3390/ijms222111568 - 26 Oct 2021

Cited by 9 | Viewed by 2838

Abstract

miRNAs and lncRNAs do not encode proteins, but they play an important role in the regulation of gene expression. They differ in length, biogenesis, and mode of action. In this work, we focus on the selected miRNAs and lncRNAs involved in the regulation [...] Read more.

miRNAs and lncRNAs do not encode proteins, but they play an important role in the regulation of gene expression. They differ in length, biogenesis, and mode of action. In this work, we focus on the selected miRNAs and lncRNAs involved in the regulation of myogenesis and muscle regeneration. We present selected miRNAs and lncRNAs that have been shown to control myogenic differentiation and show that manipulation of their levels could be used to improve myogenic differentiation of various types of stem and progenitor cells. Finally, we discuss how physical activity affects miRNA and lncRNA expression and how it affects muscle well-being. Full article

(This article belongs to the Special Issue microRNA Regulatory Network)

19 pages, 13811 KiB

Open AccessReview

Emerging Functions for snoRNAs and snoRNA-Derived Fragments

by Maliha Wajahat, Cameron Peter Bracken and Ayla Orang

Int. J. Mol. Sci. 2021, 22(19), 10193; https://doi.org/10.3390/ijms221910193 - 22 Sep 2021

Cited by 72 | Viewed by 8627

Abstract

The widespread implementation of mass sequencing has revealed a diverse landscape of small RNAs derived from larger precursors. Whilst many of these are likely to be byproducts of degradation, there are nevertheless metabolically stable fragments derived from tRNAs, rRNAs, snoRNAs, and other non-coding [...] Read more.

The widespread implementation of mass sequencing has revealed a diverse landscape of small RNAs derived from larger precursors. Whilst many of these are likely to be byproducts of degradation, there are nevertheless metabolically stable fragments derived from tRNAs, rRNAs, snoRNAs, and other non-coding RNA, with a number of examples of the production of such fragments being conserved across species. Coupled with specific interactions to RNA-binding proteins and a growing number of experimentally reported examples suggesting function, a case is emerging whereby the biological significance of small non-coding RNAs extends far beyond miRNAs and piRNAs. Related to this, a similarly complex picture is emerging of non-canonical roles for the non-coding precursors, such as for snoRNAs that are also implicated in such areas as the silencing of gene expression and the regulation of alternative splicing. This is in addition to a body of literature describing snoRNAs as an additional source of miRNA-like regulators. This review seeks to highlight emerging roles for such non-coding RNA, focusing specifically on “new” roles for snoRNAs and the small fragments derived from them. Full article

(This article belongs to the Special Issue microRNA Regulatory Network)

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28 pages, 3151 KiB

Open AccessReview

miRNA Regulatory Functions in Farm Animal Diseases, and Biomarker Potentials for Effective Therapies

by Duy N. Do, Pier-Luc Dudemaine, Manisha Mathur, Prashanth Suravajhala, Xin Zhao and Eveline M. Ibeagha-Awemu

Int. J. Mol. Sci. 2021, 22(6), 3080; https://doi.org/10.3390/ijms22063080 - 17 Mar 2021

Cited by 37 | Viewed by 5039

Abstract

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression post-transcriptionally by targeting either the 3′ untranslated or coding regions of genes. They have been reported to play key roles in a wide range of biological processes. The recent remarkable developments of transcriptomics [...] Read more.

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression post-transcriptionally by targeting either the 3′ untranslated or coding regions of genes. They have been reported to play key roles in a wide range of biological processes. The recent remarkable developments of transcriptomics technologies, especially next-generation sequencing technologies and advanced bioinformatics tools, allow more in-depth exploration of messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs), including miRNAs. These technologies have offered great opportunities for a deeper exploration of miRNA involvement in farm animal diseases, as well as livestock productivity and welfare. In this review, we provide an overview of the current knowledge of miRNA roles in major farm animal diseases with a particular focus on diseases of economic importance. In addition, we discuss the steps and future perspectives of using miRNAs as biomarkers and molecular therapy for livestock disease management as well as the challenges and opportunities for understanding the regulatory mechanisms of miRNAs related to disease pathogenesis. Full article

(This article belongs to the Special Issue microRNA Regulatory Network)

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