scholarly journals The miRNA biogenesis pathway prevents inappropriate expression of injury response genes in developing and adult Schwann cells

Glia ◽  
2018 ◽  
Vol 66 (12) ◽  
pp. 2632-2644 ◽  
Author(s):  
Deniz Gökbuget ◽  
Jorge A. Pereira ◽  
Lennart Opitz ◽  
Dominik Christe ◽  
Tobias Kessler ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Mirna Biogenesis ◽  
Injury Response ◽  
Inappropriate Expression ◽  
Mirna Biogenesis Pathway

MicroRNA annotation in plants: current status and challenges

2021 ◽  
Author(s):  
Yongxin Zhao ◽  
Zheng Kuang ◽  
Ying Wang ◽  
Lei Li ◽  
Xiaozeng Yang
Keyword(s):  
Small Rna ◽  
Signal To Noise Ratio ◽  
Current Status ◽  
Mirna Biogenesis ◽  
Plant Mirnas ◽  
Signal To Noise ◽  
Advantages And Disadvantages ◽  
Plant Mirna ◽  
History Of ◽  
Mirna Biogenesis Pathway

Abstract Last two decades, the studies on microRNAs (miRNAs) and the numbers of annotated miRNAs in plants and animals have surged. Herein, we reviewed the current progress and challenges of miRNA annotation in plants. Via the comparison of plant and animal miRNAs, we pinpointed out the difficulties on plant miRNA annotation and proposed potential solutions. In terms of recalling the history of methods and criteria in plant miRNA annotation, we detailed how the major progresses made and evolved. By collecting and categorizing bioinformatics tools for plant miRNA annotation, we surveyed their advantages and disadvantages, especially for ones with the principle of mimicking the miRNA biogenesis pathway by parsing deeply sequenced small RNA (sRNA) libraries. In addition, we summarized all available databases hosting plant miRNAs, and posted the potential optimization solutions such as how to increase the signal-to-noise ratio (SNR) in these databases. Finally, we discussed the challenges and perspectives of plant miRNA annotations, and indicated the possibilities offered by an all-in-one tool and platform according to the integration of artificial intelligence.

scholarly journals Sepiapterin alleviates impaired gastric nNOS function in spontaneous diabetic female rodents through NRF2 mRNA turnover and miRNA biogenesis pathway

2018 ◽  
Vol 315 (6) ◽  
pp. G980-G990 ◽  
Author(s):  
Pandu R. Gangula ◽  
Kishore B. Challagundla ◽  
Kalpana Ravella ◽  
Sutapa Mukhopadhyay ◽  
Vijayakumar Chinnathambi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Gastric Motility ◽  
Neuronal Nitric Oxide Synthase ◽  
Mrna Turnover ◽  
Mirna Biogenesis ◽  
Related Factor ◽  
Downstream Signaling ◽  
Oxide Synthase ◽  
Mirna Biogenesis Pathway

An impaired nitrergic system and altered redox signaling contribute to gastric dysmotility in diabetics. Our earlier studies show that NF-E2-related factor 2 (NRF2) and phase II antioxidant enzymes play a vital role in gastric neuronal nitric oxide synthase (nNOS) function. This study aims to investigate whether supplementation of sepiapterin (SEP), a precursor for tetrahydrobiopterin (BH4) (a cofactor of NOS) via the salvage pathway, restores altered nitrergic systems and redox balance in spontaneous diabetic (DB) female rats. Twelve-week spontaneous DB and age-matched, non-DB rats, with and without dietary SEP (daily 20 mg/kg body wt for 10 days) treatment, were used in this study. Gastric antrum muscular tissues were excised to investigate the effects of SEP in nitrergic relaxation and the nNOS-nitric oxide (NO)-NRF2 pathway(s). Dietary SEP supplementation significantly ( P < 0.05) reverted diabetes-induced changes in nNOS dimerization and function; nitric oxide (NO) downstream signaling molecules; HSP-90, a key regulator of nNOSα activity and dimerization; miRNA-28 that targets NRF2 messenger RNA (mRNA), and levels of microRNA (miRNA) biogenesis pathway components, such as DGCR8 (DiGeorge Syndrome Critical Region Gene 8) and TRBP (HIV1-1 transactivating response RNA-binding protein). These findings emphasize the importance of the BH4 pathway in regulating gastric motility functions in DB animals by modulating nNOSα dimerization in association with changes in enteric NRF2 and NO downstream signaling. Our results also identify a new pathway, wherein SEP regulates NRF2 mRNA turnover by suppressing elevated miRNA-28, which could be related to alterations in miRNA biogenesis pathway components. NEW & NOTEWORTHY This study is the first to show a causal link between NF-E2-related factor 2 (NRF2) and neuronal nitric oxide synthase (nNOS) in gastric motility function. Our data demonstrate that critical regulators of the miRNA biosynthetic pathway are upregulated in the diabetic (DB) setting; these regulators were rescued by sepiapterin (SEP) treatment. Finally, we show that low dihydrofolate reductase expression may lead to impaired nNOS dimerization/function-reduced nitric oxide downstream signaling and elevate oxidative stress by suppressing the NRF2/phase II pathway through miRNA; SEP treatment restored all of the above in DB gastric muscular tissue. We suggest that tetrahydrobiopterin supplementation may be a useful therapy for patients with diabetes, as well as women with idiopathic gastroparesis.

Hypoxia micromanages glioma

2016 ◽  
Vol 9 (411) ◽  
pp. ec11-ec11
Author(s):  
Leslie K. Ferrarelli
Keyword(s):  
Mirna Biogenesis ◽  
Adaptation To Hypoxia ◽  
Hypoxic Conditions ◽  
Poor Patient ◽  
Glioma Initiating Cells ◽  
Expression Of Genes ◽  
Multiple Processes ◽  
Functional Blocking ◽  
Mirna Biogenesis Pathway ◽  
Poor Patient Survival

Glioblastoma (GBM) is an aggressive brain cancer that is often characterized by a hypoxic microenvironment. Hypoxia-inducible factors (HIFs) transcriptionally promote multiple processes associated with GBM progression. Hu et al. found that hypoxia-induced HIF1α in GBM increased the production of a microRNA (miRNA) that drove the proliferation of glioma-initiating cells (GICs), a subpopulation of cells that may promote the growth and recurrence of GBM. The abundance of various miRNAs was increased by hypoxia, but only the functional blocking of miR-215 decreased the proliferation of cultured patient tumor–derived GICs in intracranial xenografts in mice. The amount of mature miR-215 and pre-miR-215, but not that of pri-miR-215, was increased in GICs cultured under hypoxic conditions, suggesting that the production of miR-215 was enhanced at a posttranscriptional step in the miRNA biogenesis pathway. However, the abundance of the Drosha and Dicer complexes that mediate this step was not increased by hypoxia. HIF1α, the abundance of which was increased in hypoxic GICs, interacted with the Drosha complex on pri-miR-215, and silencing HIF1α prevented the hypoxia-induced increase in the amount of miR-215 in GICs. Microarray and reporter analyses in GICs revealed that miR-215 targets and silences the mRNA encoding the histone demethylase KDM1B. Knocking down KDM1B in GICs increased neurosphere formation and the expression of genes associated with glucose metabolism in GIC cultures, and endothelial cells cultured in medium conditioned by KDM1B-deficient GICs exhibited increased migration. Decreased abundance of KDM1B in GBM patient tumors correlated with increased expression of HIF1A and miR-215 and with poor patient survival. The findings identify a miRNA biogenesis-targeted pathway through which hypoxia promotes GBM growth.J. Hu, T. Sun, H. Wang, Z. Chen, S. Wang, L. Yuan, T. Liu, H.-R. Li, P. Wang, Y. Feng, Q. Wang, R. E. McLendon, A. H. Friedman, S. T. Keir, D. D. Bigner, J. Rathmell, X.-d. Fu, Q.-J. Li, H. Wang, X.-F. Wang, MiR-215 is induced post-transcriptionally via HIF-Drosha complex and mediates glioma-initiating cell adaptation to hypoxia by targeting KDM1B. Cancer Cell 29, 49–60 (2016). [PubMed]

scholarly journals The human box C/D snoRNA U3 is a miRNA source and miR-U3 regulates expression of sortin nexin 27

2020 ◽  
Vol 48 (14) ◽  
pp. 8074-8089
Author(s):  
Nicolas Lemus-Diaz ◽  
Rafael Rinaldi Ferreira ◽  
Katherine E Bohnsack ◽  
Jens Gruber ◽  
Markus T Bohnsack
Keyword(s):  
Mirna Biogenesis ◽  
Loop Structure ◽  
Stem Loop ◽  
Stem Loop Structure ◽  
Eukaryotic Gene Expression ◽  
Eukaryotic Gene ◽  
Rna Fragments ◽  
Reporter Assays ◽  
Mirna Biogenesis Pathway

Abstract MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression and their dysfunction is often associated with cancer. Alongside the canonical miRNA biogenesis pathway involving stepwise processing and export of pri- and pre-miRNA transcripts by the microprocessor complex, Exportin 5 and Dicer, several alternative mechanisms of miRNA production have been described. Here, we reveal that the atypical box C/D snoRNA U3, which functions as a scaffold during early ribosome assembly, is a miRNA source. We show that a unique stem–loop structure in the 5′ domain of U3 is processed to form short RNA fragments that associate with Argonaute. miR-U3 production is independent of Drosha, and an increased amount of U3 in the cytoplasm in the absence of Dicer suggests that a portion of the full length snoRNA is exported to the cytoplasm where it is efficiently processed into miRNAs. Using reporter assays, we demonstrate that miR-U3 can act as a low proficiency miRNA in vivo and our data support the 3′ UTR of the sortin nexin SNX27 mRNA as an endogenous U3-derived miRNA target. We further reveal that perturbation of U3 snoRNP assembly induces miR-U3 production, highlighting potential cross-regulation of target mRNA expression and ribosome production.

scholarly journals An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

2017 ◽  
Vol 114 (25) ◽  
pp. E4961-E4970 ◽  
Author(s):  
Ivan Martinez ◽  
Karen E. Hayes ◽  
Jamie A. Barr ◽  
Abby D. Harold ◽  
Mingyi Xie ◽  
...  
Keyword(s):  
Cell Biology ◽  
Alternative Pathway ◽  
Human Fibroblasts ◽  
Cellular Growth ◽  
Mirna Biogenesis ◽  
Mirna Processing ◽  
Quiescent Cells ◽  
Cellular Quiescence ◽  
Processing Factors ◽  
Mirna Biogenesis Pathway

The reversible state of proliferative arrest known as “cellular quiescence” plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNA-processing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7-trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1–dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest.

Centenarians maintain miRNA biogenesis pathway while it is impaired in octogenarians

2017 ◽  
Vol 168 ◽  
pp. 54-57 ◽  
Author(s):  
C. Borrás ◽  
E. Serna ◽  
J. Gambini ◽  
M. Inglés ◽  
J. Vina
Keyword(s):  
Mirna Biogenesis ◽  
Mirna Biogenesis Pathway

scholarly journals Regulation of signalling by microRNAs

2012 ◽  
Vol 40 (1) ◽  
pp. 26-30 ◽  
Author(s):  
Roi Avraham ◽  
Yosef Yarden
Keyword(s):  
Transcriptional Repression ◽  
Signal Propagation ◽  
Cellular Responses ◽  
Mirna Biogenesis ◽  
Extracellular Signals ◽  
Genetic Switches ◽  
Control Stability ◽  
External Stimuli ◽  
Mirna Biogenesis Pathway

Stringent regulation of biochemical signalling pathways involves feedback and feedforward loops, which underlie robust cellular responses to external stimuli. Regulation occurs in all horizontal layers of signalling networks, primarily by proteins that mediate internalization of receptor–ligand complexes, dephosphorylation of kinases and their substrates, as well as transcriptional repression. Recent studies have unveiled the role of miRNAs (microRNAs), post-transcriptional regulators that control mRNA stability, as key modulators of signal propagation. By acting as genetic switches or fine-tuners, miRNAs can directly and multiply regulate cellular outcomes in response to diverse extracellular signals. Conversely, signalling networks temporally control stability, biogenesis and abundance of miRNAs, by regulating layers of the miRNA biogenesis pathway. In the present mini-review, we use a set of examples to illustrate the extensive interdependence between miRNAs and signalling networks.

scholarly journals A dicer-independent miRNA biogenesis pathway that requires Ago catalysis

Nature ◽  
2010 ◽  
Vol 465 (7298) ◽  
pp. 584-589 ◽  
Author(s):  
Sihem Cheloufi ◽  
Camila O. Dos Santos ◽  
Mark M. W. Chong ◽  
Gregory J. Hannon
Keyword(s):  
Mirna Biogenesis ◽  
Mirna Biogenesis Pathway

scholarly journals Salvage Therapy for Multiple Myeloma with Lenalidomide-Based Regimens: Impact of Single Nucleotide Polymorphisms Related to miRNA Pathways

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2045-2045 ◽  
Author(s):  
Carlos Fernández de Larrea ◽  
Tania Díaz ◽  
María Teresa Cibeira ◽  
Natalia Tovar ◽  
Alfons Navarro ◽  
...  
Keyword(s):  
Target Genes ◽  
Autologous Transplantation ◽  
Mirna Biogenesis ◽  
Nucleotide Polymorphisms ◽  
Advisory Committees ◽  
Single Nucleotide ◽  
Predictors Of Response ◽  
Grant Support ◽  
First Relapse ◽  
Mirna Biogenesis Pathway

Abstract Introduction: Multiple myeloma (MM) remains an incurable disease for most patients. Thus, sequential therapy when relapse or progression after first line is almost always needed. Immunomodulatory agents derived from thalidomide such as lenalidomide, has several antitumoral effects including anti-proliferative and immune-modulation by binding the intracellular protein cereblon. Lenalidomide has been approved for the treatment of relapsed or refractory MM in Europe and USA. The possibility of using biological predictors of response with this regimen could be promising. A group of genetic normal variations in DNA, mainly single nucleotide polymorphisms (SNPs), have been described in association with response to treatment in MM. A distinctive group of polymorphisms is constituted by SNPs in microRNAs (miRNA) processing machinery in miRNA precursor molecules and in miRNA binding sites, known as miRSNPs, that we have associated with response to autologous transplantation and bortezomib. The aim of this study was to ascertain the outcome of patients with relapsed myeloma treated with lenalidomide in a tertiary hospital as to investigate the prognostic impact of 9 miRSNPs located either in MM related miRNAs target genes or in miRNA biogenesis pathway proteins Methods: One hundred and three patients (54M/49F; median age 65 years, range 30 to 86) with relapsed MM after at least one treatment regimen were treated from November 2003 to January 2014 with lenalidomide plus dexamethasone. Median follow-up for alive patients was 3 years. Patients had received a median number of 2 treatment lines (range 1 – 6), but with no lenalidomide-based regimens. Genomic DNA was isolated from bone marrow slides using a commercial kit (Qiagen). The genes and SNPs evaluated in genomic DNA by allelic discrimination (TaqMan assays) were KRT81 (rs3660), FAM179b (rs1053667), MIR146A (rs2910164), MIR196A2 (rs11614913), MIR149 (rs2292832) and MIR423 (rs6505162) for miRNA target genes, and RAN (rs14035), TRBP (rs784567) and XPO5 (rs11077) for miRNA biogenesis pathway. These genes were selected based on their potential impact on prognosis in solid tumors in previous reports. Results: Overall response (OR) was achieved in 55.4% of the patients (complete remission 6.8%, partial response 40.8% and minor response 7.8%), while 16 (15.5%) and 26 (25.2%) showed no response (NR) or progressive disease (PD), respectively. 4 patients (3.9%) died before response could be evaluated. The median progression-free survival (PFS) after lenalidomide therapy was 8.1 months (95% CI 7.3 to 8.9), with a median overall survival (OS) of 2.3 years (95% CI 1.5 to 3.2). OS was significantly shorter in those patients not reaching at least MR (1 vs. 3.7 years; p<0.0001). Six patients did not progress during the first 5 years of treatment: two have died for unrelated causes; two progressed biologically but no requiring further treatments and the remaining two are in continued response while on therapy. Only 8 responding patients (7.8%) in whom therapy with lenalidomide was discontinued received re-treatment with lenalidomide at progression. OS was significantly longer in patients with SNP in FAM179b (p=0.041) (Figure 1) and MIR196A2 (p=0.01) (Figure 2), with a trend for MIR149 (p=0.117). In the two first SNPs, there were also a significant impact in PFS after lenalidomide regimen (p=0.024 and p=0.018). Interestingly, these miRSNPs have not shown the same impact as previously reported when autologous transplantation or bortezomib are used, where XPO5 is the crucial gene. Other factors associated with longer OS included lenalidomide at first relapse vs. subsequent lines (p=0.002), IgG isotype (p=0.044), normal serum LDH (p=0.032) and a trend for creatinine lower than 2 mg/dL (p=0.08) at diagnosis. In a multivariate analysis for OS, only the use of lenalidomide at first relapse (HR 2, 95% IC 1.04-3.9; p=0.039) and SNP in MIR196A2 (HR 1.86, 95% IC 1.03-3.4; p=0.04) remained at significant level. Conclusions: Lenalidomide plus dexamethasone is a very active regimen when used in daily clinical practice, particularly at the time of first relapse. A small subgroup of patients can remain disease-free for more than 5 years. Some SNPs in miRNA target genes (FAM179b and, particularly, MIR196A) could be useful as potential predictors of response. Figure 1 Figure 1. Disclosures Fernández de Larrea: Celgene: Consultancy, Honoraria. Cibeira:Celgene: Consultancy, Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Jiménez:Janssen: Honoraria. Bladé:Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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