Translational Repression and eIF4A2 Activity Are Critical for MicroRNA-Mediated Gene Regulation

Science ◽  
2013 ◽  
Vol 340 (6128) ◽  
pp. 82-85 ◽  
Author(s):  
H. A. Meijer ◽  
Y. W. Kong ◽  
W. T. Lu ◽  
A. Wilczynska ◽  
R. V. Spriggs ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Molecular Mechanisms ◽  
Translational Repression ◽  
Messenger Rnas ◽  
Primary Event ◽  
Control Gene Expression ◽  
Target Sites ◽  
Key Factor ◽  
Mrna Destabilization ◽  
Translational Inhibition

MicroRNAs (miRNAs) control gene expression through both translational repression and degradation of target messenger RNAs (mRNAs). However, the interplay between these processes and the precise molecular mechanisms involved remain unclear. Here, we show that translational inhibition is the primary event required for mRNA degradation. Translational inhibition depends on miRNAs impairing the function of the eIF4F initiation complex. We define the RNA helicase eIF4A2 as the key factor of eIF4F through which miRNAs function. We uncover a correlation between the presence of miRNA target sites in the 3′ untranslated region (3′UTR) of mRNAs and secondary structure in the 5′UTR and show that mRNAs with unstructured 5′UTRs are refractory to miRNA repression. These data support a linear model for miRNA-mediated gene regulation in which translational repression via eIF4A2 is required first, followed by mRNA destabilization.

scholarly journals 1456. Resistance Mechanisms of Tigecycline in Enterococcus faecalis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S730-S731
Author(s):  
Bing Bai ◽  
Zewen Wen ◽  
Zhiwei Lin ◽  
Tam Vincent H ◽  
Zhijian Yu
Keyword(s):  
Enterococcus Faecalis ◽  
Molecular Mechanisms ◽  
Genetic Mutations ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Whole Genome ◽  
Synonymous Mutations ◽  
Target Sites ◽  
Parental Isolate ◽  
Resistant Strains

Abstract Background Enterococcus faecalis have been regarded as one of the leading causes of the nosocomial infections worldwide. Tigecycline (TGC) is considered as a choice of last resort for the treatment of infections caused by multidrug-resistant E. faecalis, however, the emergence of TGC non-susceptibility has posted the therapeutic challenge. Non-susceptibility in clinical strains could be due to resistance (MIC >0.5 mg/l) or heteroresistance. Therefore, this study aimed to understand the underlying molecular mechanisms of TGC resistance and heteroresistance in E. faecalis. Methods In vitro induction experiments were carried out under TGC pressure with two TGC- sensitive E. faecalis strains. Heteroresistance was evaluated by population analysis profiling (PAP) in 270 clinical TGC- sensitive E. faecalis strains. TGC susceptibility was determined by the agar dilution method. Resistance and heteroresistance mechanisms were investigated by identifying genetic mutations in tetracycline (Tet) target sites and susceptibility testing in the presence of the efflux protein inhibitors phenylalanine-arginine-β-naphthylamide (PaβN) and carbonyl cyanide m chlorophenylhydrazine (CCCP). Comparison of single nucleotide polymorphism in the whole genome between the parental isolate and two TGC-resistant strains were investigated by next-generation sequencing. Results No mutations in Tet target sites in seven TGC heteroresistant strains were present, whereas the mutations in Tet target sites of seven TGC-resistant E. faecalis were frequently found (Table 1). TGC MICs in heteroresistant strains were reduced by CCCP (Table 2). Whole genome sequencing revealed the same non-synonymous mutations and transcoding deletions in the exons of several genes encoding for various enzymes or transfer systems (Table 3). Table 1. The characteristics of the antimicrobial susceptibility, resistance mechanism of TGC-induced resistant isolates Table 2. Characteristics of clinical heteroresistant mother E. faecalis strains and heteroresistance-derived E. faecalis clones Table 3. List of mutation-related genes, amino acids and proteins by comparison of whole genome between the parental isolate and the TGC-induced resistant strains Conclusion Our data indicated that the main mechanism of TGC heteroresistance in E. faecalis might be associated with the efflux pumps. TGC resistance in E. faecalis was associated with mutations in the 16SrRNA site or 30S ribosome protein S10. The genetic mutations in several enzymes and transfer systems might also participate in the resistance development to TGC in E. faecalis. Disclosures All Authors: No reported disclosures

scholarly journals Vitamin E beyond Its Antioxidant Label

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 634
Author(s):  
Anca Ungurianu ◽  
Anca Zanfirescu ◽  
Georgiana Nițulescu ◽  
Denisa Margină
Keyword(s):  
Vitamin E ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Protective Effects ◽  
Cellular Effects ◽  
Inflammatory Status ◽  
Anti Cancer ◽  
Key Factor ◽  
Exciting Potential ◽  
Underlying Mechanisms

Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal-based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component.

scholarly journals Novel Gene Regulation in Normal and Abnormal Spermatogenesis

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 666
Author(s):  
Li Du ◽  
Wei Chen ◽  
Zixin Cheng ◽  
Si Wu ◽  
Jian He ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Leydig Cells ◽  
Molecular Mechanisms ◽  
New Technologies ◽  
Genetic Regulation ◽  
Myoid Cells ◽  
Epigenetic Factors ◽  
Future Directions ◽  
New Genes ◽  
Human Spermatogenesis

Spermatogenesis is a complex and dynamic process which is precisely controlledby genetic and epigenetic factors. With the development of new technologies (e.g., single-cell RNA sequencing), increasingly more regulatory genes related to spermatogenesis have been identified. In this review, we address the roles and mechanisms of novel genes in regulating the normal and abnormal spermatogenesis. Specifically, we discussed the functions and signaling pathways of key new genes in mediating the proliferation, differentiation, and apoptosis of rodent and human spermatogonial stem cells (SSCs), as well as in controlling the meiosis of spermatocytes and other germ cells. Additionally, we summarized the gene regulation in the abnormal testicular microenvironment or the niche by Sertoli cells, peritubular myoid cells, and Leydig cells. Finally, we pointed out the future directions for investigating the molecular mechanisms underlying human spermatogenesis. This review could offer novel insights into genetic regulation in the normal and abnormal spermatogenesis, and it provides new molecular targets for gene therapy of male infertility.

scholarly journals The roles and mechanisms of hypoxia in liver fibrosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jingyao Cai ◽  
Min Hu ◽  
Zhiyang Chen ◽  
Zeng Ling
Keyword(s):  
Quality Of Life ◽  
Liver Fibrosis ◽  
Theoretical Basis ◽  
Liver Diseases ◽  
Molecular Mechanisms ◽  
Clinical Intervention ◽  
Chronic Liver Injury ◽  
Key Factor

AbstractLiver fibrosis occurs in response to any etiology of chronic liver injury. Lack of appropriate clinical intervention will lead to liver cirrhosis or hepatocellular carcinoma (HCC), seriously affecting the quality of life of patients, but the current clinical treatments of liver fibrosis have not been developed yet. Recent studies have shown that hypoxia is a key factor promoting the progression of liver fibrosis. Hypoxia can cause liver fibrosis. Liver fibrosis can, in turn, profoundly further deepen the degree of hypoxia. Therefore, exploring the role of hypoxia in liver fibrosis will help to further understand the process of liver fibrosis, and provide the theoretical basis for its diagnosis and treatment, which is of great significance to avoid further deterioration of liver diseases and protect the life and health of patients. This review highlights the recent advances in cellular and molecular mechanisms of hypoxia in developments of liver fibrosis.

scholarly journals The Rho-family GTPase OsRac1 controls rice grain size and yield by regulating cell division

2019 ◽  
Vol 116 (32) ◽  
pp. 16121-16126 ◽  
Author(s):  
Ying Zhang ◽  
Yan Xiong ◽  
Renyi Liu ◽  
Hong-Wei Xue ◽  
Zhenbiao Yang
Keyword(s):  
Grain Size ◽  
Cell Division ◽  
Grain Yield ◽  
Molecular Mechanisms ◽  
Grain Filling ◽  
High Yield ◽  
Rice Grain ◽  
Rop Gtpase ◽  
Key Factor ◽  
Grain Width

Grain size is a key factor for determining grain yield in crops and is a target trait for both domestication and breeding, yet the mechanisms underlying the regulation of grain size are largely unclear. Here we show that the grain size and yield of rice (Oryza sativa) is positively regulated by ROP GTPase (Rho-like GTPase from plants), a versatile molecular switch modulating plant growth, development, and responses to the environment. Overexpression of rice OsRac1ROP not only increases cell numbers, resulting in a larger spikelet hull, but also accelerates grain filling rate, causing greater grain width and weight. As a result, OsRac1 overexpression improves grain yield in O. sativa by nearly 16%. In contrast, down-regulation or deletion of OsRac1 causes the opposite effects. RNA-seq and cell cycle analyses suggest that OsRac1 promotes cell division. Interestingly, OsRac1 interacts with and regulates the phosphorylation level of OsMAPK6, which is known to regulate cell division and grain size in rice. Thus, our findings suggest OsRac1 modulates rice grain size and yield by influencing cell division. This study provides insights into the molecular mechanisms underlying the control of rice grain size and suggests that OsRac1 could serve as a potential target gene for breeding high-yield crops.

Regulation of β myosin heavy chain, c-myc and c-fos proto-oncogenes in thyroid hormone-induced hypertrophy of the rat myocardium

1993 ◽  
Vol 84 (1) ◽  
pp. 61-67 ◽  
Author(s):  
N. K. Green ◽  
M. D. Gammage ◽  
J. A. Franklyn ◽  
A. M. Heagerty ◽  
M. C. Sheppard
Keyword(s):  
Thyroid Hormone ◽  
Right Ventricular ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Transcriptional Level ◽  
Messenger Rnas ◽  
Hypertrophic Response ◽  
Left And Right

1. In order to investigate the molecular mechanisms determining the hypertrophic response of the ventricular myocardium to thyroid hormone administration, changes in left and right ventricular expression of the c-myc, c-fos and H-ras proto-oncogenes in response to treatment with 3,3′,5-tri-iodothyronine were defined. 2. Adult female Wistar rats were treated with daily subcutaneous injections of 3,3′,5-tri-iodothyronine (50 μg) for 1, 3, 7 or 14 days (n = 6 in each treatment group) and the results from 3,3′,5-tri-iodothyronine-treated animals were compared with those obtained from untreated controls (n = 6). Changes in the weight of the left and right ventricles in response to 3,3′,5-tri-iodothyronine treatment were measured; changes in expression of the c-myc, c-fos and H-ras proto-oncogenes were determined in parallel by measurement of specific messenger RNAs by Northern and dot hybridization, as well as changes in expression of β myosin heavy chain messenger RNA. 3. Treatment with 3,3′,5-tri-iodothyronine resulted in increases in both left and right ventricular weights after 3 days, an effect maintained up to 14 days. Despite an increase in left ventricular weight, levels of β myosin heavy chain, c-myc, c-fos and H-ras mRNAs in the left ventricle were unchanged; in contrast, an increase in right ventricular weight was associated with increased expression of β myosin heavy chain, c-myc and c-fos messenger RNAs. 4. These specific ventricular changes in gene expression, in the face of a hypertrophic response of both ventricles to 3,3′,5-tri-iodothyronine, suggest that the cardiac growth response to thyroid hormones reflects the well-documented secondary haemodynamic influences rather than direct gene regulatory actions of 3,3′,5-tri-iodothyronine at the transcriptional level on the genes studied. Changes in right ventricular proto-oncogene and β myosin heavy chain expression may in turn reflect an increase in right ventricular pressure load.

scholarly journals Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

2021 ◽  
Author(s):  
Mouhamed Alsaqati ◽  
Brittany A Davis ◽  
Jamie Wood ◽  
Megan Jones ◽  
Lora Jones ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Psychiatric Disorders ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Mirna Gene ◽  
Neuronal Gene ◽  
Kleefstra Syndrome ◽  
Elevated Expression ◽  
H3k9 Dimethylation ◽  
Human Ipsc

SummaryGenetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

scholarly journals Antioxidant Responses and Gene Expression in Bermudagrass under Cold Stress

2014 ◽  
Vol 139 (6) ◽  
pp. 699-705 ◽  
Author(s):  
Jibiao Fan ◽  
Jing Ren ◽  
Weixi Zhu ◽  
Erick Amombo ◽  
Jinmin Fu ◽  
...  
Keyword(s):  
Cold Stress ◽  
Molecular Mechanisms ◽  
Cynodon Dactylon ◽  
Sugar Content ◽  
Soluble Sugar ◽  
Molecular Alteration ◽  
Antioxidant Genes ◽  
Dramatic Decline ◽  
Malondialdehyde Content ◽  
Key Factor

Cold stress is a key factor limiting resource use in bermudagrass (Cynodon dactylon). Under cold stress, bermudagrass growth is severely inhibited and the leaves undergo chlorosis. Therefore, rigorous investigation on the physiological and molecular mechanisms of cold stress in this turf species is urgent. The objective of this study was to investigate the physiological and molecular alteration in wild bermudagrass under cold stress, particularly the changes of transpiration rate, soluble sugar content, enzyme activities, and expression of antioxidant genes. Wild bermudagrass (C. dactylon) was planted in plastic pots (each 10 cm tall and 8 cm in diameter) filled with matrix (brown coal soil:sand 1:1) and treated with 4 °C in a growth chamber. The results displayed a dramatic decline in the growth and transpiration rates of the wild bermudagrass under 4 °C temperature. Simultaneously, cold severely destabilized the cell membrane as indicated by increased malondialdehyde content and electrolyte leakage value. Superoxide dismutase and peroxidase activities were higher in the cold regime than the control. The expression of antioxidant genes including MnSOD, Cu/ZnSOD, POD, and APX was vividly up-regulated after cold stress. In summary, our results contributed to the understanding of the role of the antioxidant system in bermudagrass’ response to cold.

scholarly journals Common genetic risk variants identified in the SPARK cohort implicate DDHD2 as a novel autism risk gene

2020 ◽  
Author(s):  
Nana Matoba ◽  
Dan Liang ◽  
Huaigu Sun ◽  
Nil Aygün ◽  
Jessica C. McAfee ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Association Study ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Risk Variants ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Gene Regulatory

AbstractBackgroundAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of three common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) using the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD.MethodsWe performed an association study on 6,222 case-pseudocontrol pairs from SPARK and meta-analyzed with a previous GWAS. We integrated gene regulatory annotations to map non-coding risk variants to their regulated genes. Further, we performed a massively parallel reporter assay (MPRA) to identify causal variant(s) within a novel risk locus.ResultsWe identified one novel GWS locus from the SPARK GWAS. The meta-analysis identified four significant loci, including an additional novel locus. We observed significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. The MPRA identified one variant at the novel locus with strong impacts on gene regulation (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and pre-natal brains.ConclusionsBy integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

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