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5458 KiB

Open AccessArticle

Long Non-Coding RNA NEAT1 Associates with SRp40 to Temporally Regulate PPARγ2 Splicing during Adipogenesis in 3T3-L1 Cells

by Denise R. Cooper, Gay Carter, Pengfei Li, Rehka Patel, James E. Watson and Niketa A. Patel

Genes 2014, 5(4), 1050-1063; https://doi.org/10.3390/genes5041050 - 27 Nov 2014

Cited by 107 | Viewed by 9992

Abstract

Long non-coding (lnc) RNAs serve a multitude of functions in cells. NEAT1 RNA is a highly abundant 4 kb lncRNA in nuclei, and coincides with paraspeckles, nuclear domains that control sequestration of paraspeckle proteins. We examined NEAT1 RNA levels and its function in [...] Read more.

Long non-coding (lnc) RNAs serve a multitude of functions in cells. NEAT1 RNA is a highly abundant 4 kb lncRNA in nuclei, and coincides with paraspeckles, nuclear domains that control sequestration of paraspeckle proteins. We examined NEAT1 RNA levels and its function in 3T3-L1 cells during differentiation to adipocytes. Levels of NEAT1 transcript, measured by RT-PCR, fluctuated in a temporal manner over the course of differentiation that suggested its role in alternative splicing of PPARγ mRNA, the major transcription factor driving adipogenesis. When cells were induced to differentiate by a media cocktail of insulin, dexamethasone, and isobutylmethyxanthine (IBMX) on Day 0, NEAT1 levels dropped on Day 4, when the PPARγ2 variant was spliced and when terminal differentiation occurs The appearance of PPARγ2 coordinates with the PPARγ1 variant to drive differentiation of adipocytes. SiRNA used to deplete NEAT1 resulted in the inability of cells to phosphorylate the serine/arginine-rich splicing protein, SRp40. SiRNA treatment for SRp40 resulted in dysregulation of PPARγ1 and, primarily, PPARγ2 mRNA levels. SRp40 associated with NEAT1, as shown by RNA-IP on days 0 and 8, but decreased on day 4, and concentrations increased over that of IgG control. Overexpression of SRp40 increased PPARγ2, but not γ1. Although lncRNA MALAT1 has been investigated in SR protein function, NEAT1 has not been shown to bind SR proteins for phosphorylation such that alternative splicing results. The ability of cells to increase phosphorylated SR proteins for PPARγ2 splicing suggests that fluxes in NEAT1 levels during adipogenesis regulate alternative splicing events. Full article

(This article belongs to the Special Issue miRNA Regulation)

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10384 KiB

Open AccessArticle

Enterococcus faecalis Infection and Reactive Oxygen Species Down-Regulates the miR-17-92 Cluster in Gastric Adenocarcinoma Cell Culture

by Jesper A. B. Strickertsson, Lene Juel Rasmussen and Lennart Friis-Hansen

Genes 2014, 5(3), 726-738; https://doi.org/10.3390/genes5030726 - 28 Aug 2014

Cited by 26 | Viewed by 7659

Abstract

Chronic inflammation due to bacterial overgrowth of the stomach predisposes to the development of gastric cancer and is also associated with high levels of reactive oxygen species (ROS). In recent years increasing attention has been drawn to microRNAs (miRNAs) due to their role [...] Read more.

Chronic inflammation due to bacterial overgrowth of the stomach predisposes to the development of gastric cancer and is also associated with high levels of reactive oxygen species (ROS). In recent years increasing attention has been drawn to microRNAs (miRNAs) due to their role in the pathogenesis of many human diseases including gastric cancer. Here we studied the impact of infection by the gram-positive bacteria Enterococcus faecalis (E. faecalis) on global miRNA expression as well as the effect of ROS on selected miRNAs. Human gastric adenocarcinoma cell line MKN74 was infected with living E. faecalis for 24 h or for 5 days or with E. faecalis lysate for 5 days. The miRNA expression was examined by microarray analysis using Affymetrix GeneChip miRNA Arrays. To test the effect of ROS, MKN74 cells were treated with 100 mM tert-Butyl hydroperoxide (TBHP). Following 5 days of E. faecalis infection we found 91 differentially expressed miRNAs in response to living bacteria and 2 miRNAs responded to E. faecalis lysate. We verified the down-regulation of the miR-17-92 and miR-106-363 clusters and of other miRNAs involved in the oxidative stress-response by qRT-PCR. We conclude that only infection by living E. faecalis bacteria caused a significant global response in miRNA expression in the MKN74 cell culture. E. faecalis infection as well as ROS stimulation down-regulated the expression of the miR-17-92 cluster. We believe that these changes could reflect a general response of gastric epithelial cells to bacterial infections. Full article

(This article belongs to the Special Issue miRNA Regulation)

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Open AccessArticle

Genetic versus Non-Genetic Regulation of miR-103, miR-143 and miR-483-3p Expression in Adipose Tissue and Their Metabolic Implications—A Twin Study

by Jette Bork-Jensen, Anne Cathrine Baun Thuesen, Claus Heiner Bang-Bertelsen, Louise Groth Grunnet, Flemming Pociot, Henning Beck-Nielsen, Susan E. Ozanne, Pernille Poulsen and Allan Vaag

Genes 2014, 5(3), 508-517; https://doi.org/10.3390/genes5030508 - 09 Jul 2014

Cited by 22 | Viewed by 7285

Abstract

Murine models suggest that the microRNAs miR-103 and miR-143 may play central roles in the regulation of subcutaneous adipose tissue (SAT) and development of type 2 diabetes (T2D). The microRNA miR-483-3p may reduce adipose tissue expandability and cause ectopic lipid accumulation, insulin resistance [...] Read more.

Murine models suggest that the microRNAs miR-103 and miR-143 may play central roles in the regulation of subcutaneous adipose tissue (SAT) and development of type 2 diabetes (T2D). The microRNA miR-483-3p may reduce adipose tissue expandability and cause ectopic lipid accumulation, insulin resistance and T2D. We aimed to explore the genetic and non-genetic factors that regulate these microRNAs in human SAT, and to investigate their impact on metabolism in humans. Levels of miR-103, miR-143 and miR-483-3p were measured in SAT biopsies from 244 elderly monozygotic and dizygotic twins using real-time PCR. Heritability estimates were calculated and multiple regression analyses were performed to study associations between these microRNAs and measures of metabolism, as well as between these microRNAs and possible regulating factors. We found that increased BMI was associated with increased miR-103 expression levels. In addition, the miR-103 levels were positively associated with 2 h plasma glucose levels and hemoglobin A1c independently of BMI. Heritability estimates for all three microRNAs were low. In conclusion, the expression levels of miR-103, miR-143 and miR-483-3p in adipose tissue are primarily influenced by non-genetic factors, and miR-103 may be involved in the development of adiposity and control of glucose metabolism in humans. Full article

(This article belongs to the Special Issue miRNA Regulation)

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Review

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Open AccessReview

Regulation of Pancreatic Beta Cell Stimulus-Secretion Coupling by microRNAs

by Jonathan L. S. Esguerra, Inês G. Mollet, Vishal A. Salunkhe, Anna Wendt and Lena Eliasson

Genes 2014, 5(4), 1018-1031; https://doi.org/10.3390/genes5041018 - 06 Nov 2014

Cited by 35 | Viewed by 10363

Abstract

Increased blood glucose after a meal is countered by the subsequent increased release of the hypoglycemic hormone insulin from the pancreatic beta cells. The cascade of molecular events encompassing the initial sensing and transport of glucose into the beta cell, culminating with the [...] Read more.

Increased blood glucose after a meal is countered by the subsequent increased release of the hypoglycemic hormone insulin from the pancreatic beta cells. The cascade of molecular events encompassing the initial sensing and transport of glucose into the beta cell, culminating with the exocytosis of the insulin large dense core granules (LDCVs) is termed “stimulus-secretion coupling.” Impairment in any of the relevant processes leads to insufficient insulin release, which contributes to the development of type 2 diabetes (T2D). The fate of the beta cell, when exposed to environmental triggers of the disease, is determined by the possibility to adapt to the new situation by regulation of gene expression. As established factors of post-transcriptional regulation, microRNAs (miRNAs) are well-recognized mediators of beta cell plasticity and adaptation. Here, we put focus on the importance of comprehending the transcriptional regulation of miRNAs, and how miRNAs are implicated in stimulus-secretion coupling, specifically those influencing the late stages of insulin secretion. We suggest that efficient beta cell adaptation requires an optimal balance between transcriptional regulation of miRNAs themselves, and miRNA-dependent gene regulation. The increased knowledge of the beta cell transcriptional network inclusive of non-coding RNAs such as miRNAs is essential in identifying novel targets for the treatment of T2D. Full article

(This article belongs to the Special Issue miRNA Regulation)

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Open AccessReview

The Role of MicroRNAs in Diabetic Complications—Special Emphasis on Wound Healing

by João Moura, Elisabet Børsheim and Eugenia Carvalho

Genes 2014, 5(4), 926-956; https://doi.org/10.3390/genes5040926 - 29 Sep 2014

Cited by 103 | Viewed by 14485

Abstract

Overweight and obesity are major problems in today’s society, driving the prevalence of diabetes and its related complications. It is important to understand the molecular mechanisms underlying the chronic complications in diabetes in order to develop better therapeutic approaches for these conditions. Some [...] Read more.

Overweight and obesity are major problems in today’s society, driving the prevalence of diabetes and its related complications. It is important to understand the molecular mechanisms underlying the chronic complications in diabetes in order to develop better therapeutic approaches for these conditions. Some of the most important complications include macrovascular abnormalities, e.g., heart disease and atherosclerosis, and microvascular abnormalities, e.g., retinopathy, nephropathy and neuropathy, in particular diabetic foot ulceration. The highly conserved endogenous small non-coding RNA molecules, the micro RNAs (miRNAs) have in recent years been found to be involved in a number of biological processes, including the pathogenesis of disease. Their main function is to regulate post-transcriptional gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation, suppression of translation or even gene activation. These molecules are promising therapeutic targets and demonstrate great potential as diagnostic biomarkers for disease. This review aims to describe the most recent findings regarding the important roles of miRNAs in diabetes and its complications, with special attention given to the different phases of diabetic wound healing. Full article

(This article belongs to the Special Issue miRNA Regulation)

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Open AccessReview

The Role of microRNAs in Mitochondria: Small Players Acting Wide

by Filipe V. Duarte, Carlos M. Palmeira and Anabela P. Rolo

Genes 2014, 5(4), 865-886; https://doi.org/10.3390/genes5040865 - 26 Sep 2014

Cited by 107 | Viewed by 11945

Abstract

MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that act as post-transcriptional gene regulators. They can inhibit target protein-coding genes, through repressing messenger RNA (mRNA) translation or promoting their degradation. miRNAs were initially found to be originated from nuclear genome and exported to [...] Read more.

MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that act as post-transcriptional gene regulators. They can inhibit target protein-coding genes, through repressing messenger RNA (mRNA) translation or promoting their degradation. miRNAs were initially found to be originated from nuclear genome and exported to cytosol; where they exerted most of their actions. More recently, miRNAs were found to be present specifically in mitochondria; even originated there from mitochondrial DNA, regulating in a direct manner genes coding for mitochondrial proteins, and consequently mitochondrial function. Since miRNAs are recognized as major players in several biological processes, they are being considered as a key to better understand, explain, and probably prevent/cure not only the pathogenesis of multifactorial diseases but also mitochondrial dysfunction and associated diseases. Here we review some of the molecular mechanisms purported for miRNA actions in several biological processes, particularly the miRNAs acting in mitochondria or in mitochondria-related mechanisms. Full article

(This article belongs to the Special Issue miRNA Regulation)

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9398 KiB

Open AccessReview

Functional Role of the microRNA-200 Family in Breast Morphogenesis and Neoplasia

by Bylgja Hilmarsdottir, Eirikur Briem, Jon Thor Bergthorsson, Magnus Karl Magnusson and Thorarinn Gudjonsson

Genes 2014, 5(3), 804-820; https://doi.org/10.3390/genes5030804 - 11 Sep 2014

Cited by 46 | Viewed by 8583

Abstract

Branching epithelial morphogenesis is closely linked to epithelial-to-mesenchymal transition (EMT), a process important in normal development and cancer progression. The miR-200 family regulates epithelial morphogenesis and EMT through a negative feedback loop with the ZEB1 and ZEB2 transcription factors. miR-200 inhibits expression of [...] Read more.

Branching epithelial morphogenesis is closely linked to epithelial-to-mesenchymal transition (EMT), a process important in normal development and cancer progression. The miR-200 family regulates epithelial morphogenesis and EMT through a negative feedback loop with the ZEB1 and ZEB2 transcription factors. miR-200 inhibits expression of ZEB1/2 mRNA, which in turn can down-regulate the miR-200 family that further results in down-regulation of E-cadherin and induction of a mesenchymal phenotype. Recent studies show that the expression of miR-200 genes is high during late pregnancy and lactation, thereby indicating that these miRs are important for breast epithelial morphogenesis and differentiation. miR-200 genes have been studied intensively in relation to breast cancer progression and metastasis, where it has been shown that miR-200 members are down-regulated in basal-like breast cancer where the EMT phenotype is prominent. There is growing evidence that the miR-200 family is up-regulated in distal breast metastasis indicating that these miRs are important for colonization of metastatic breast cancer cells through induction of mesenchymal to epithelial transition. The dual role of miR-200 in primary and metastatic breast cancer is of interest for future therapeutic interventions, making it important to understand its role and interacting partners in more detail. Full article

(This article belongs to the Special Issue miRNA Regulation)

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Open AccessReview

by Anja Elaine Sørensen, Marie Louise Wissing, Sofia Salö, Anne Lis Mikkelsen Englund and Louise Torp Dalgaard

Genes 2014, 5(3), 684-708; https://doi.org/10.3390/genes5030684 - 25 Aug 2014

Cited by 133 | Viewed by 11429

Abstract

Polycystic ovary syndrome (PCOS) is the most common, though heterogeneous, endocrine aberration in women of reproductive age, with high prevalence and socioeconomic costs. The syndrome is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism, as well as being associated with infertility, insulin resistance, [...] Read more.

Polycystic ovary syndrome (PCOS) is the most common, though heterogeneous, endocrine aberration in women of reproductive age, with high prevalence and socioeconomic costs. The syndrome is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism, as well as being associated with infertility, insulin resistance, chronic low-grade inflammation and an increased life time risk of type 2 diabetes. MicroRNAs (miRNAs) are small, non-coding RNAs that are able to regulate gene expression at the post-transcriptional level. Altered miRNA levels have been associated with diabetes, insulin resistance, inflammation and various cancers. Studies have shown that circulating miRNAs are present in whole blood, serum, plasma and the follicular fluid of PCOS patients and that they might serve as potential biomarkers and a new approach for the diagnosis of PCOS. In this review, recent work on miRNAs with respect to PCOS will be summarized. Our understanding of miRNAs, particularly in relation to PCOS, is currently at a very early stage, and additional studies will yield important insight into the molecular mechanisms behind this complex and heterogenic syndrome. Full article

(This article belongs to the Special Issue miRNA Regulation)

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Open AccessReview

Computational Methods for MicroRNA Target Prediction

by Semih Ekimler and Kaniye Sahin

Genes 2014, 5(3), 671-683; https://doi.org/10.3390/genes5030671 - 22 Aug 2014

Cited by 76 | Viewed by 9681

Abstract

MicroRNAs (miRNAs) have been identified as one of the most important molecules that regulate gene expression in various organisms. miRNAs are short, 21–23 nucleotide-long, single stranded RNA molecules that bind to 3' untranslated regions (3' UTRs) of their target mRNAs. In general, they [...] Read more.

MicroRNAs (miRNAs) have been identified as one of the most important molecules that regulate gene expression in various organisms. miRNAs are short, 21–23 nucleotide-long, single stranded RNA molecules that bind to 3' untranslated regions (3' UTRs) of their target mRNAs. In general, they silence the expression of their target genes via degradation of the mRNA or by translational repression. The expression of miRNAs, on the other hand, also varies in different tissues based on their functions. It is significantly important to predict the targets of miRNAs by computational approaches to understand their effects on the regulation of gene expression. Various computational methods have been generated for miRNA target prediction but the resulting lists of candidate target genes from different algorithms often do not overlap. It is crucial to adjust the bioinformatics tools for more accurate predictions as it is equally important to validate the predicted target genes experimentally. Full article

(This article belongs to the Special Issue miRNA Regulation)

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Open AccessReview

MicroRNAs as Mediators of the Ageing Process

by Lorna W. Harries

Genes 2014, 5(3), 656-670; https://doi.org/10.3390/genes5030656 - 20 Aug 2014

Cited by 87 | Viewed by 9550

Abstract

Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about [...] Read more.

Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about by epigenetic and mRNA processing changes, loss of protein homeostasis, altered nutrient signaling, mitochondrial dysfunction, stem cell exhaustion, premature cellular senescence and altered intracellular communication. Like practically all other cellular processes, genes associated in features of ageing are regulated by miRNAs. In this review, I will outline each of the features of ageing, together with examples of specific miRNAs that have been demonstrated to be involved in each one. This will demonstrate the interconnected nature of the regulation of transcripts involved in human ageing, and the role of miRNAs in this process. Definition of the factors involved in degeneration of organismal, tissue and cellular homeostasis may provide biomarkers for healthy ageing and increase understanding of the processes that underpin the ageing process itself. Full article

(This article belongs to the Special Issue miRNA Regulation)

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