Dicing the Disease with Dicer: The Implications of Dicer Ribonuclease in Human Pathologies

Gene expression dictates fundamental cellular processes and its de-regulation leads to pathological conditions. A key contributor to the fine-tuning of gene expression is Dicer, an RNA-binding protein (RBPs) that forms complexes and affects transcription by acting at the post-transcriptional level via the targeting of mRNAs by Dicer-produced small non-coding RNAs. This review aims to present the contribution of Dicer protein in a wide spectrum of human pathological conditions, including cancer, neurological, autoimmune, reproductive and cardiovascular diseases, as well as viral infections. Germline mutations of Dicer have been linked to Dicer1 syndrome, a rare genetic disorder that predisposes to the development of both benign and malignant tumors, but the exact correlation of Dicer protein expression within the different cancer types is unclear, and there are contradictions in the data. Downregulation of Dicer is related to Geographic atrophy (GA), a severe eye-disease that is a leading cause of blindness in industrialized countries, as well as to psychiatric and neurological diseases such as depression and Parkinson’s disease, respectively. Both loss and upregulation of Dicer protein expression is implicated in severe autoimmune disorders, including psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis and autoimmune thyroid diseases. Loss of Dicer contributes to cardiovascular diseases and causes defective germ cell differentiation and reproductive system abnormalities in both sexes. Dicer can also act as a strong antiviral with a crucial role in RNA-based antiviral immunity. In conclusion, Dicer is an essential enzyme for the maintenance of physiology due to its pivotal role in several cellular processes, and its loss or aberrant expression contributes to the development of severe human diseases. Further exploitation is required for the development of novel, more effective Dicer-based diagnostic and therapeutic strategies, with the goal of new clinical benefits and better quality of life for patients.

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Competing Endogenous RNAs in Cervical Carcinogenesis: A New Layer of Complexity

Processes ◽

10.3390/pr9060991 ◽

2021 ◽

Vol 9 (6) ◽

pp. 991

Author(s):

Fernanda Costa Brandão Berti ◽

Sara Cristina Lobo-Alves ◽

Camila de Freitas Oliveira-Toré ◽

Amanda Salviano-Silva ◽

Karen Brajão de Oliveira ◽

...

Keyword(s):

Gene Expression ◽

Fine Tuning ◽

Molecular Networks ◽

Cervical Carcinogenesis ◽

Molecular Changes ◽

Cellular Processes ◽

Target Mrnas ◽

Competing Endogenous Rnas ◽

Cervical Cells ◽

Post Transcriptional Regulation

MicroRNAs (miRNAs) regulate gene expression by binding to complementary sequences within target mRNAs. Apart from working ‘solo’, miRNAs may interact in important molecular networks such as competing endogenous RNA (ceRNA) axes. By competing for a limited pool of miRNAs, transcripts such as long noncoding RNAs (lncRNAs) and mRNAs can regulate each other, fine-tuning gene expression. Several ceRNA networks led by different lncRNAs—described here as lncRNA-mediated ceRNAs—seem to play essential roles in cervical cancer (CC). By conducting an extensive search, we summarized networks involved in CC, highlighting the major impacts of such dynamic molecular changes over multiple cellular processes. Through the sponging of distinct miRNAs, some lncRNAs as HOTAIR, MALAT1, NEAT1, OIP5-AS1, and XIST trigger crucial molecular changes, ultimately increasing cell proliferation, migration, invasion, and inhibiting apoptosis. Likewise, several lncRNAs seem to be a sponge for important tumor-suppressive miRNAs (as miR-140-5p, miR-143-3p, miR-148a-3p, and miR-206), impairing such molecules from exerting a negative post-transcriptional regulation over target mRNAs. Curiously, some of the involved mRNAs code for important proteins such as PTEN, ROCK1, and MAPK1, known to modulate cell growth, proliferation, apoptosis, and adhesion in CC. Overall, we highlight important lncRNA-mediated functional interactions occurring in cervical cells and their closely related impact on cervical carcinogenesis.

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Abstract P104: Reactivation of Embryonic Gene Program due to CUG Repeat RNA Expression in Myotonic Dystrophy

Circulation Research ◽

10.1161/res.109.suppl_1.ap104 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Auinash Kalsotra ◽

Ravi Singh ◽

Chad Creighton ◽

Thomas Cooper

Keyword(s):

Gene Expression ◽

Myotonic Dystrophy ◽

Rna Binding ◽

Rna Binding Proteins ◽

Expression Patterns ◽

Causative Mutation ◽

Inherited Disease ◽

Aberrant Expression ◽

Organ Systems ◽

General Response

Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease that affects multiple organ systems. Cardiac involvement, which is characterized by conduction defects and arrhythmias, is the second leading cause of death in DM1 patients. The causative mutation is a CTG expansion in the 3' untranslated region of DMPK gene resulting in aberrant expression of CUG repeat RNA that accumulates into nuclear foci and causes misregulation in alternative splicing. Here we show that heart-specific and inducible expression of CUG repeat RNA in a DM1 mouse model results in global reactivation of embryonic gene expression program in adult heart that is distinct from a general hypertrophic stress response. Using q-PCR TaqMan arrays, we identified 54 miRNAs that were differentially expressed in DM1 mouse hearts one week following induction of CUG repeat RNA. Interestingly, 83% (45/54) of them exhibited a developmental shift in expression towards the embryonic pattern. Because over 90% (41/45) of them were down regulated within 72 hr after induction of repeat RNA and only 2/22 examined decreased in two unrelated mouse models of heart disease, we conclude their reduced expression is specific to DM1 and not simply a general response to cardiac injury. Microarray studies revealed a developmental switch not only in the miRNA expression patterns but also a pervasive shift in mRNA steady state levels of a number of genes to embryonic stage. Intriguingly, we found that loss of MBNL1 or gain of CELF1 activity, two major RNA binding proteins disrupted in DM1, are not driving the miRNA misregulation since their expression is indistinguishable between wild type, MBNL1 knock out and CELF1 over expressing mice. Moreover, comparable decrease in ten out of ten primary miRNA transcripts examined suggests loss of expression is not due to a processing defect. Instead, we discovered that adult-to-embryonic shift in expression of select micro- and messenger RNAs in DM1 heart occurs due to specific inactivation of a Mef2 transcriptional program. We are currently determining causal contributions of this Mef2-miRNA circuitry in the developmental reprogramming of gene expression in DM1 as well as its direct role in cardiac manifestations of this disease.

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Cold-induced RNA-binding protein (CIRBP) regulates the expression of Src-associated during mitosis of 68 kDa (Sam68) and extracellular signal-regulated kinases (ERK) during heat stress-induced testicular injury

Reproduction Fertility and Development ◽

10.1071/rd20253 ◽

2020 ◽

Vol 32 (18) ◽

pp. 1357

Author(s):

Chengcheng Xu ◽

Dandan Ke ◽

Liping Zou ◽

Nianyu Li ◽

Yingying Wang ◽

...

Keyword(s):

Gene Expression ◽

Heat Stress ◽

Protein Expression ◽

Rna Binding ◽

Cell Model ◽

Binding Protein ◽

Rna Binding Protein ◽

Protein Levels ◽

Extracellular Signal ◽

Testicular Injury

In this study, the ability of cold-induced RNA-binding protein (CIRBP) to regulate the expression of Src-associated during mitosis of 68 kDa (Sam68) and extracellular signal-regulated kinases (ERK) in the mouse testis and mouse primary spermatocytes (GC-2spd cell line) before and after heat stress was examined to explore the molecular mechanism by which CIRBP decreases testicular injury. A mouse testicular hyperthermia model, a mouse primary spermatocyte hyperthermia model and a low CIRBP gene-expression cell model were constructed and their relevant parameters were analysed. The mRNA and protein levels of CIRBP and Sam68 were significantly decreased in the 3-h and 12-h testicular heat-stress groups, extracellular signal-regulated kinase 1/2 (ERK1/2) protein expression was not significantly affected but phospho-ERK1/2 protein levels were significantly decreased. GC-2spd cellular heat-stress results showed that the mRNA and protein concentrations of CIRBP and Sam68 were reduced 48h after heat stress. In the low CIRBP gene-expression cell model, CIRBP protein expression was significantly decreased. Sam68 mRNA expression was significantly decreased only at the maximum transfection concentration of 50nM and Sam68 protein expression was not significantly affected. These findings suggest that CIRBP may regulate the expression of Sam68 at the transcriptional level and the expression of phospho-ERK1/2 protein, both of which protect against heat-stress-induced testicular injury in mice.

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238 RNA BINDING PROTEIN EXPRESSION IN CULTURED EARLY BOVINE EMBRYOS

Reproduction Fertility and Development ◽

10.1071/rdv22n1ab238 ◽

2010 ◽

Vol 22 (1) ◽

pp. 277

Author(s):

L. A. Favetta ◽

E. Van de Laar ◽

W. A. King ◽

J. LaMarre

Keyword(s):

Gene Expression ◽

Protein Expression ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Bovine Embryo ◽

Rt Pcr ◽

Control Of Gene Expression ◽

Morula Stage ◽

Bovine Oocytes

The control of gene expression in the early embryo requires a highly regulated turnover of specific mRNA, particularly those of maternal origin, as the embryo becomes transcriptionally autonomous. In cattle, the period during which maternal transcripts persist can last 72 to 96 h or longer, suggesting a dynamic, regulated interplay between factors that protect transcripts before this point and those that subsequently facilitate decay. Some decay pathways for specific embryonic transcripts are now known, but many are not. In somatic cells, mRNA decay is often mediated by interactions between defined sequence elements (ARE) in the 3′ untranslated region of important target genes and specific RNA-binding proteins (AUBP) that promote or inhibit decay of the associated transcript. These have not been extensively characterized in embryos. We hypothesized that changes in the pattern of expression of one or several AUBP in the developing bovine embryo would support a role for these proteins in mRNA turnover and the control of gene expression. We, therefore, evaluated the expression of different AUBP (HuR, AUF1, TTP) in bovine oocytes and early embryos in vitro. Bovine oocytes obtained at slaughter were matured, fertilized, and cultured using standard protocols. Oocytes and embryos from different stages were either placed in Trizol for subsequent RNA isolation and RT-PCR analysis or fixed in 4% paraformaldehyde and subsequently processed for immunohistochemical detection of AUBP. Analysis by RT-PCR revealed that AUF1, an mRNA destabilizing protein, was expressed at all stages examined (immature oocyte, mature oocyte, 2 to 4 cells, 8 to 16 cells, morulae, and blastocyst) except in morulae. Another mRNA destabilizing protein, TTP, was expressed at the morula stage only. An mRNA stabilizing factor, HuR, was expressed at all stages except the morula. Immunohistochemical analysis revealed that the pattern of protein expression for AUF1 and TTP essentially mirrored that observed at the RNA level as detected by RT-PCR. Together, these results show that AUBP expression in the early bovine embryo is dynamic, with RNA-binding proteins present at all times during development and changes in expression evident at the morula stage. This suggests that modification of presynthesized (i.e. maternal) AUBP is likely to control mRNA decay during the maternal to embryonic transition (8-cell stage) and that the expression of TTP at the morula stage might mark the onset of embryonic control of mRNA stability. Research was supported by NSERC, OMAFRA, and the Canada Research Chairs Program.

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RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21186835 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6835

Author(s):

Jonas Weiße ◽

Julia Rosemann ◽

Vanessa Krauspe ◽

Matthias Kappler ◽

Alexander W. Eckert ◽

...

Keyword(s):

Gene Expression ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Invasion And Metastasis ◽

Protein Coding ◽

Oral Cancers ◽

Cellular Processes ◽

Post Transcriptional Regulation

Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target RNAs, i.e., alternative splicing, polyadenylation, stability and turnover, localization, or translation as well as editing and chemical modification, thereby tuning gene expression programs of diverse cellular processes such as cell survival and malignant spread. Importantly, metastases are the major cause of cancer-associated deaths in general, and particularly in oral cancers, which account for 2% of the global cancer mortality. However, the roles and architecture of RBPs and RBP-controlled expression networks during the diverse steps of the metastatic cascade are only incompletely understood. In this review, we will offer a brief overview about RBPs and their general contribution to post-transcriptional regulation of gene expression. Subsequently, we will highlight selected examples of RBPs that have been shown to play a role in oral cancer cell migration, invasion, and metastasis. Last but not least, we will present targeting strategies that have been developed to interfere with the function of some of these RBPs.

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Correlation between Dexamethasone and miRNAs in the regulation of apoptosis, drug-resistance, and metastasis of cancer cell

Current Molecular Medicine ◽

10.2174/1566524020666200925155614 ◽

2020 ◽

Vol 20 ◽

Author(s):

Leila Mohammadi ◽

Bashir Mosayyebi ◽

Mahsa Imani ◽

Nosratollah Zarghami ◽

Effat Alizadeh ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Cell ◽

Regulatory Networks ◽

Fine Tuning ◽

Cellular Processes ◽

Pathological Conditions ◽

Cell Progression ◽

Cancer Cell Survival ◽

Non Coding Rnas ◽

Corticosteroid Hormone

: Dexamethasone (Dex) is a synthetic corticosteroid hormone derived from the steroid chemical group and is applicable in treating several pathological conditions like inflammation, autoimmune disease, and malignancies. Recent investigations on the mechanism of action of Dex and its possible interactions with other cellular regulatory networks may help explanation of the inconsistent effects of Dex in cancer treatment. Fine-tuning regulation of essential post-transcriptional regulators such as microRNA (miRNAs) has indispensable impacts on modulating fundamental cellular processes including gene expression, cell proliferation, cell cycling, and apoptosis. Dex appears to act as a double-edged sword on cancer cell progression and metastasis through regulating miRNA networks. As a proof of concept, recent investigations have proved Dex to be effective in cancer-treating either individually or in combination with other therapeutical compounds while several evidences have point to the controversial effects of Dex in the promotion of cancer cell survival, drug-resistance, and metastasis. In addition, it has been proved that other non-coding RNAs (ncRNAs) can also be directly or indirectly affected by Dex. In this review, we aimed to investigate the controversial effect of Dex on the cancer-related miRNAs.

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Therapeutic Approaches and Role of ncRNAs in Cardiovascular Disorders and Insulin Resistance

BioMed Research International ◽

10.1155/2017/4078346 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Kalupahana Irushi Pamodya Liyanage ◽

Gamage Upeksha Ganegoda

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Cardiovascular Diseases ◽

Gene Expression Regulation ◽

Therapeutic Approaches ◽

Gene Expressions ◽

Diagnostic Biomarkers ◽

Cellular Processes ◽

Regulatory Functions

Diseases resulting from alterations in gene expressions through mutations in the genes or through changes in the gene expression regulation could be identified through the analysis of RNA expressions. ncRNAs play a significant role in regulation of the gene expression by controlling the expression levels of the coding RNAs and other cellular processes. Discoveries have shown that the human genome is encoded with sequences responsible for the transcription of thousands of ncRNAs. Even though the studies conducted on ncRNAs are still at initial stages, facts established so far display biomarkers that confirm their relationship with certain diseases such as cancers, cardiovascular diseases, and insulin resistance. These studies have been facilitated with high throughput modern sequencing techniques such as microarrays and RNA sequencing. The data obtained through the above analysis are processed with the aid of existing databases, to deduce conclusions on different diagnostic biomarkers and therapeutic targets for specific diseases. This review focuses on the association of ncRNAs in disease prediction, focusing mainly on cardiovascular diseases and disorders caused by insulin resistance. The report also analyzes regulatory functions of ncRNAs and novel approaches used in disease therapeutics.

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Dynamic mRNP Remodeling in Response to Internal and External Stimuli

Biomolecules ◽

10.3390/biom10091310 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1310 ◽

Cited By ~ 1

Author(s):

Kathi Zarnack ◽

Sureshkumar Balasubramanian ◽

Michael P. Gantier ◽

Vladislav Kunetsky ◽

Michael Kracht ◽

...

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Rna Binding ◽

Environmental Changes ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Cellular Processes ◽

Messenger Ribonucleoprotein ◽

Transcriptional Modulation ◽

External Stimuli

Signal transduction and the regulation of gene expression are fundamental processes in every cell. RNA-binding proteins (RBPs) play a key role in the post-transcriptional modulation of gene expression in response to both internal and external stimuli. However, how signaling pathways regulate the assembly of RBPs with mRNAs remains largely unknown. Here, we summarize observations showing that the formation and composition of messenger ribonucleoprotein particles (mRNPs) is dynamically remodeled in space and time by specific signaling cascades and the resulting post-translational modifications. The integration of signaling events with gene expression is key to the rapid adaptation of cells to environmental changes and stress. Only a combined approach analyzing the signal transduction pathways and the changes in post-transcriptional gene expression they cause will unravel the mechanisms coordinating these important cellular processes.

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Roles of the Pumilio domain protein PUF3 in Trypanosoma brucei growth and differentiation

Parasitology ◽

10.1017/s003118202000092x ◽

2020 ◽

Vol 147 (11) ◽

pp. 1171-1183

Author(s):

K. Kamanyi Marucha ◽

C. Clayton

Keyword(s):

Gene Expression ◽

Trypanosoma Brucei ◽

Rna Binding ◽

Ectopic Expression ◽

Fine Tuning ◽

Growth Defect ◽

Binding Studies ◽

Procyclic Form ◽

Delayed Differentiation ◽

Domain Protein

AbstractTrypanosomes strongly rely on post-transcriptional mechanisms to control gene expression. Several Opisthokont Pumilio domain proteins are known to suppress expression when bound to mRNAs. The Trypanosoma brucei Pumilio domain protein PUF3 is a cytosolic mRNA-binding protein that suppresses expression when tethered to a reporter mRNA. RNA-binding studies showed that PUF3 preferentially binds to mRNAs with a classical Pumilio-domain recognition motif, UGUA[U/C]AUU. RNA-interference-mediated reduction of PUF3 in bloodstream forms caused a minor growth defect, but the transcriptome was not affected. Depletion of PUF3 also slightly delayed differentiation to the procyclic form. However, both PUF3 genes could be deleted in cultured bloodstream- and procyclic-form trypanosomes. Procyclic forms without PUF3 also grew somewhat slower than wild-type, but ectopic expression of C-terminally tagged PUF3 impaired their viability. PUF3 was not required for RBP10-induced differentiation of procyclic forms to bloodstream forms. Mass spectrometry revealed no PUF3 binding partners that might explain its suppressive activity. We conclude that PUF3 may have a role in fine-tuning gene expression. Since PUF3 is conserved in all Kinetoplastids, including those that do not infect vertebrates, we suggest that it might confer advantages within the invertebrate host.

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Epitranscriptomic profiling across cell types reveals associations between APOBEC1-mediated RNA editing, gene expression outcomes, and cellular function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1714227114 ◽

2017 ◽

Vol 114 (50) ◽

pp. 13296-13301 ◽

Cited By ~ 18

Author(s):

Violeta Rayon-Estrada ◽

Dewi Harjanto ◽

Claire E. Hamilton ◽

Yamina A. Berchiche ◽

Emily Conn Gantman ◽

...

Keyword(s):

Gene Expression ◽

Rna Editing ◽

Rna Stability ◽

Cell Types ◽

Fine Tuning ◽

Mrna Editing ◽

Cellular Processes ◽

Small Set ◽

Functional Relevance ◽

Editing Enzyme

Epitranscriptomics refers to posttranscriptional alterations on an mRNA sequence that are dynamic and reproducible, and affect gene expression in a similar way to epigenetic modifications. However, the functional relevance of those modifications for the transcript, the cell, and the organism remain poorly understood. Here, we focus on RNA editing and show that Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-1 (APOBEC1), together with its cofactor RBM47, mediates robust editing in different tissues. The majority of editing events alter the sequence of the 3′UTR of targeted transcripts, and we focus on one cell type (monocytes) and on a small set of highly edited transcripts within it to show that editing alters gene expression by modulating translation (but not RNA stability or localization). We further show that specific cellular processes (phagocytosis and transendothelial migration) are enriched for transcripts that are targets of editing and that editing alters their function. Finally, we survey bone marrow progenitors and demonstrate that common monocyte progenitor cells express high levels of APOBEC1 and are susceptible to loss of the editing enzyme. Overall, APOBEC1-mediated transcriptome diversification is required for the fine-tuning of protein expression in monocytes, suggesting an epitranscriptomic mechanism for the proper maintenance of homeostasis in innate immune cells.

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