scholarly journals Selenium-Related Transcriptional Regulation of Gene Expression

2018 ◽  
Author(s):  
Mikko J. Lammi ◽  
Chengjuan Qu
Keyword(s):  
Stop Codon ◽  
Regulation Of Gene Expression ◽  
Selenium Deficiency ◽  
Mrna Levels ◽  
Translation Elongation ◽  
Nonsense Mediated Decay ◽  
Specific Complex ◽  
System Functioning ◽  
The One ◽  
Selenoprotein Mrnas

Selenium is a trace metal essential to human health, and its deficiency has been related to, for instance, cardiovascular and myodegenerative diseases, infertility and osteochondropathy Kashin-Beck disease. It is incorporated as selenocysteine to selenoproteins, which protect against reactive oxygen and nitrogen species. They also participate in the activation of thyroid hormone, and play a role in immune system functioning. The synthesis and incorporation of selenocysteine occurs via a special mechanism, which differs from the one used for standard amino acids. The codon for selenocysteine is the regular in-frame stop codon, which can be passed by specific complex machinery participating in translation elongation and termination. This includes the presence of selenocysteine insertion sequence (SECIS) in the 3’-untranslated part of the selenoprotein mRNAs. Selenium deficiency is known to control both selenoprotein and non-selenoprotein transcriptomes. Nonsense-mediated decay is involved in the regulation of selenoprotein mRNA levels, both other mechanisms are also possible.

scholarly journals Selenium-Related Transcriptional Regulation of Gene Expression

2018 ◽  
Vol 19 (9) ◽  
pp. 2665 ◽  
Author(s):  
Mikko Lammi ◽  
Chengjuan Qu
Keyword(s):  
Transcriptional Regulation ◽  
Stop Codon ◽  
Regulation Of Gene Expression ◽  
The Body ◽  
Mrna Levels ◽  
Messenger Rnas ◽  
Nonsense Mediated Decay ◽  
Proteomic Data ◽  
The One ◽  
Beck Disease

The selenium content of the body is known to control the expression levels of numerous genes, both so-called selenoproteins and non-selenoproteins. Selenium is a trace element essential to human health, and its deficiency is related to, for instance, cardiovascular and myodegenerative diseases, infertility and osteochondropathy called Kashin–Beck disease. It is incorporated as selenocysteine to the selenoproteins, which protect against reactive oxygen and nitrogen species. They also participate in the activation of the thyroid hormone, and play a role in immune system functioning. The synthesis and incorporation of selenocysteine occurs via a special mechanism, which differs from the one used for standard amino acids. The codon for selenocysteine is a regular in-frame stop codon, which can be passed by a specific complex machinery participating in translation elongation and termination. This includes a presence of selenocysteine insertion sequence (SECIS) in the 3′-untranslated part of the selenoprotein mRNAs. Nonsense-mediated decay is involved in the regulation of the selenoprotein mRNA levels, but other mechanisms are also possible. Recent transcriptional analyses of messenger RNAs, microRNAs and long non-coding RNAs combined with proteomic data of samples from Keshan and Kashin–Beck disease patients have identified new possible cellular pathways related to transcriptional regulation by selenium.

scholarly journals Selenium status highly regulates selenoprotein mRNA levels for only a subset of the selenoproteins in the selenoproteome

2009 ◽  
Vol 29 (5) ◽  
pp. 329-338 ◽  
Author(s):  
Roger A. Sunde ◽  
Anna M. Raines ◽  
Kimberly M. Barnes ◽  
Jacqueline K. Evenson
Keyword(s):  
Thioredoxin Reductase ◽  
Selenium Deficiency ◽  
Underlying Mechanism ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Nonsense Mediated Decay ◽  
Liver And Kidney ◽  
Se Deficiency ◽  
Selenoprotein Mrnas ◽  
Se Status

Gpx (glutathione peroxidase)-1 enzyme activity and mRNA levels decrease dramatically in Se (selenium) deficiency, whereas other selenoproteins are less affected by Se deficiency. This hierarchy of Se regulation is not understood, but the position of the UGA selenocysteine codon is thought to play a major role in making selenoprotein mRNAs susceptible to nonsense-mediated decay. Thus in the present paper we studied the complete selenoproteome in the mouse to uncover additional selenoprotein mRNAs that are highly regulated by Se status. Mice were fed on Se-deficient, Se-marginal and Se-adequate diets (0, 0.05 and 0.2 μg of Se/g respectively) for 35 days, and selenoprotein mRNA levels in liver and kidney were determined using microarray analysis and quantitative real-time PCR analysis. Se-deficient mice had liver Se concentrations and liver Gpx1 and thioredoxin reductase activities that were 4, 3 and 3% respectively of the levels in Se-adequate mice, indicating that the mice were Se deficient. mRNAs for Selh (selenoprotein H) and Sepw1 (selenoprotein W) as well as Gpx1 were decreased by Se deficiency to <40% of Se-adequate levels. Five and two additional mRNAs were moderately down-regulated in Sedeficient liver and kidney respectively. Importantly, nine selenoprotein mRNAs in liver and fifteen selenoprotein mRNAs in the kidney were not significantly regulated by Se deficiency, clearly demonstrating that Se regulation of selenoprotein mRNAs is not a general phenomenon. The similarity of the response to Se deficiency suggests that there is one underlying mechanism responsible. Importantly, the position of the UGA codon did not predict susceptibility to Se regulation, clearly indicating that additional features are involved in causing selenoprotein mRNAs to be sensitive to Se status.

scholarly journals Efficient Incorporation of Multiple Selenocysteines Involves an Inefficient Decoding Step Serving as a Potential Translational Checkpoint and RibosomeBottleneck

2006 ◽  
Vol 26 (24) ◽  
pp. 9177-9184 ◽  
Author(s):  
Zoia Stoytcheva ◽  
Rosa M. Tujebajeva ◽  
John W. Harney ◽  
Marla J. Berry
Keyword(s):  
Untranslated Region ◽  
Stop Codon ◽  
Secondary Structures ◽  
Selenoprotein P ◽  
Secis Element ◽  
Nonsense Mediated Decay ◽  
Slowing Down ◽  
Uga Codon ◽  
Sense Codon ◽  
Selenoprotein Mrnas

ABSTRACT Selenocysteine is incorporated into proteins via “recoding” of UGA from a stop codon to a sense codon, a process that requires specific secondary structures in the 3′ untranslated region, termed selenocysteine incorporation sequence (SECIS) elements, and the protein factors that they recruit. Whereas most selenoprotein mRNAs contain a single UGA codon and a single SECIS element, selenoprotein P genes encode multiple UGAs and two SECIS elements. We have identified evolutionary adaptations in selenoprotein P genes that contribute to the efficiency of incorporating multiple selenocysteine residues in this protein. The first is a conserved, inefficiently decoded UGA codon in the N-terminal region, which appears to serve both as a checkpoint for the presence of factors required for selenocysteine incorporation and as a“ bottleneck,” slowing down the progress of elongating ribosomes. The second adaptation involves the presence of introns downstream of this inefficiently decoded UGA which confer the potential for nonsense-mediated decay when factors required for selenocysteine incorporation are limiting. Third, the two SECIS elements in selenoprotein P mRNA function with differing efficiencies, affecting both the rate and the efficiency of decoding different UGAs. The implications for how these factors contribute to the decoding of multiple selenocysteine residues are discussed.

scholarly journals Nuclear Assembly of UGA Decoding Complexes on Selenoprotein mRNAs: a Mechanism for Eluding Nonsense-Mediated Decay?

2006 ◽  
Vol 26 (5) ◽  
pp. 1795-1805 ◽  
Author(s):  
Lucia A. de Jesus ◽  
Peter R. Hoffmann ◽  
Tanya Michaud ◽  
Erin P. Forry ◽  
Andrea Small-Howard ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Stop Codon ◽  
Elongation Factor ◽  
Protein Translation ◽  
Nonsense Mediated Decay ◽  
Nuclear Assembly ◽  
Mrna Binding Protein ◽  
Two Factors ◽  
Mrna Binding ◽  
Selenoprotein Mrnas

ABSTRACT Recoding of UGA from a stop codon to selenocysteine poses a dilemma for the protein translation machinery. In eukaryotes, two factors that are crucial to this recoding process are the mRNA binding protein of the Sec insertion sequence, SBP2, and the specialized elongation factor, EFsec. We sought to determine the subcellular localization of these selenoprotein synthesis factors in mammalian cells and thus gain insight into how selenoprotein mRNAs might circumvent nonsense-mediated decay. Intriguingly, both EFsec and SBP2 localization differed depending on the cell line but significant colocalization of the two proteins was observed in cells where SBP2 levels were detectable. We identify functional nuclear localization and export signals in both proteins, demonstrate that SBP2 undergoes nucleocytoplasmic shuttling, and provide evidence that SBP2 levels and localization may influence EFsec localization. Our results suggest a mechanism for the nuclear assembly of the selenocysteine incorporation machinery that could allow selenoprotein mRNAs to circumvent nonsense-mediated decay, thus providing new insights into the mechanism of selenoprotein translation.

scholarly journals SBP2 Binding Affinity Is a Major Determinant in Differential Selenoprotein mRNA Translation and Sensitivity to Nonsense-Mediated Decay

2007 ◽  
Vol 27 (22) ◽  
pp. 7848-7855 ◽  
Author(s):  
Jeffrey E. Squires ◽  
Ilko Stoytchev ◽  
Erin P. Forry ◽  
Marla J. Berry
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Major Determinant ◽  
Mrna Levels ◽  
Nonsense Mediated Decay ◽  
Potential Factors ◽  
Mechanistic Basis ◽  
Selenoprotein Mrnas

ABSTRACT Selenoprotein mRNAs are potential targets for degradation via nonsense-mediated decay due to the presence of in-frame UGA codons that can be decoded as either selenocysteine or termination codons. When UGA decoding is inefficient, as occurs when selenium is limiting, termination occurs at these positions. Based on the predicted exon-intron structure, 14 of the 25 human selenoprotein mRNAs are predicted to be sensitive to nonsense-mediated decay. Among these, sensitivity varies widely, resulting in a hierarchy of preservation or degradation of selenoprotein mRNAs and, thus, of selenoprotein synthesis. Potential factors in dictating the hierarchy of selenoprotein synthesis are the Sec insertion sequence RNA-binding proteins, SBP2 and nucleolin. To investigate the mechanistic basis for this hierarchy and the role of these two proteins, we carried out knockdowns of SBP2 expression and assessed the effects on selenoprotein mRNA levels. We also investigated in vivo binding of selenoprotein mRNAs by SBP2 and nucleolin via immunoprecipitation of the proteins and quantitation of bound mRNAs. We report that SBP2 exhibits strong preferential binding to some selenoprotein mRNAs over others, whereas nucleolin exhibits minimal differences in binding. Thus, SBP2 is a major determinant in dictating the hierarchy of selenoprotein synthesis via differential selenoprotein mRNA translation and sensitivity to nonsense-mediated decay.

scholarly journals Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 734
Author(s):  
Xuhua Xia
Keyword(s):  
Codon Usage ◽  
Translation Initiation ◽  
Mrna Stability ◽  
Stop Codon ◽  
Translation Termination ◽  
Critical Evaluation ◽  
Immunization Programs ◽  
Translation Elongation ◽  
Different Types ◽  
Similarities And Differences

The design of Pfizer/BioNTech and Moderna mRNA vaccines involves many different types of optimizations. Proper optimization of vaccine mRNA can reduce dosage required for each injection leading to more efficient immunization programs. The mRNA components of the vaccine need to have a 5’-UTR to load ribosomes efficiently onto the mRNA for translation initiation, optimized codon usage for efficient translation elongation, and optimal stop codon for efficient translation termination. Both 5’-UTR and the downstream 3’-UTR should be optimized for mRNA stability. The replacement of uridine by N1-methylpseudourinine () complicates some of these optimization processes because is more versatile in wobbling than U. Different optimizations can conflict with each other, and compromises would need to be made. I highlight the similarities and differences between Pfizer/BioNTech and Moderna mRNA vaccines and discuss the advantage and disadvantage of each to facilitate future vaccine improvement. In particular, I point out a few optimizations in the design of the two mRNA vaccines that have not been performed properly.

scholarly journals Minerals contributing to human health and well-being

2021 ◽  
Vol 2 (1) ◽  
pp. 58-64
Author(s):  
Ekaterina V. Kulchavenya ◽  
◽  
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Cell Function ◽  
Paneth Cell ◽  
Lymphatic Vessels ◽  
Selenium Deficiency ◽  
Well Being ◽  
Gastrointestinal Infections ◽  
System Functioning ◽  
Normal Human

The gut microbiome is vital for normal human body functioning. The etiological and pathogenetic significance of increased intestinal permeability in disorders of various organs and systems seems to be certain. The term “microbiota-gut-brain axis” has been defined; the crucial role of the microbiota-gut-brain axis in neurological disorders has been confirmed. Gut microbiome not only contributes to digestion, metabolism and immunity, but also mediates sleep and mental health of the host via microbiota-gut-brain axis. Such elements as zinc and selenium are essential to maintain the microbial balance in the gut. Zinc contributes to gut homeostasis and Paneth cell function. Zinc has a direct impact on gut microbiota composition (for example, on some species of Staphylococcus), modulates gut microbiota reducing the fatal entry of bacteria into the bloodstream and lymphatic vessels. Thus, zinc alters microbiome due to direct cytotoxic / cytostatic effect on certain bacteria, such as staphylococci. Zinc possesses therapeutic effect in gastrointestinal infections and diarrhea. Bacterial translocation may be also reduced with Rebamipide possessing cytoprotective and antioxidant activity. Selenium in the form of selenoproteins has a number of functions in normal health and metabolism. Selenium contributes to immune system functioning and to progression of HIV to AIDS. Selenium deficiency results in cardiovascular diseases, infertility, myodegenerative disorders, and cognitive decline.

Effect of hypothyroidism on adenylyl cyclase activity and subtype gene expression in brown adipose tissue

1997 ◽  
Vol 273 (2) ◽  
pp. R762-R767 ◽  
Author(s):  
A. Chaudhry ◽  
J. G. Granneman
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Adenylyl Cyclase ◽  
Regulation Of Gene Expression ◽  
Mrna Levels ◽  
Adrenergic Stimulation ◽  
Functional Responses ◽  
Synergistic Interactions ◽  
Brown Adipose

Brown adipose tissue (BAT) expresses several adenylyl cyclase (AC) subtypes, and adrenergic stimulation selectively upregulates AC-III gene expression. Previous studies have described synergistic interactions between the sympathetic nervous system (SNS) and 3,5,3'-triiodothyronine (T3) on the regulation of gene expression in BAT. Because adrenergic stimulation also increases the activity of BAT type II thyroxine 5'-deiodinase (DII) and local T3 generation is important for many functional responses in BAT, we examined the effects of thyroid hormone status on the expression of various AC subtypes. Hypothyroidism selectively increased AC-III mRNA levels in BAT but not in white adipose tissue. Of the other subtypes examined, hypothyroidism did not alter AC-VI mRNA levels and slightly reduced AC-IX mRNA levels in BAT. The increase in AC-III expression was paralleled by an increase in forskolin-stimulated AC activity in BAT membranes. Sympathetic denervation of BAT abolished the increase in both AC activity and AC-III mRNA expression produced by hypothyroidism, but did not affect the expression of other subtypes. Surgical denervation also prevented the induction of AC-III in the cold-stressed euthyroid rat, but injections of T3 failed to alter AC-III expression in intact or denervated BAT. Our results indicate that T3 does not directly affect expression of AC-III. Rather, hypothyroidism increases BAT AC-III expression indirectly via an increase in sympathetic stimulation. Furthermore, our results strongly indicate that the increase in AC activity in hypothyroid BAT is due to increased expression of AC-III.

scholarly journals YY1 is a cis-regulator in the organoid models of high mammographic density

2019 ◽  
Vol 36 (6) ◽  
pp. 1663-1667 ◽  
Author(s):  
Qingsu Cheng ◽  
Mina Khoshdeli ◽  
Bradley S Ferguson ◽  
Kosar Jabbari ◽  
Chongzhi Zang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Lines ◽  
Mammographic Density ◽  
Regulatory Networks ◽  
Regulation Of Gene Expression ◽  
Human Mammary Epithelial Cell ◽  
Mammary Epithelial ◽  
Supplementary Information ◽  
Mrna Levels ◽  
High Mammographic Density

Abstract Motivation Our previous study has shown that ERBB2 is overexpressed in the organoid model of MCF10A when the stiffness of the microenvironment is increased to that of high mammographic density (MD). We now aim to identify key transcription factors (TFs) and functional enhancers that regulate processes associated with increased stiffness of the microenvironment in the organoid models of premalignant human mammary cell lines. Results 3D colony organizations and the cis-regulatory networks of two human mammary epithelial cell lines (184A1 and MCF10A) are investigated as a function of the increased stiffness of the microenvironment within the range of MD. The 3D colonies are imaged using confocal microscopy, and the morphometries of colony organizations and heterogeneity are quantified as a function of the stiffness of the microenvironment using BioSig3D. In a surrogate assay, colony organizations are profiled by transcriptomics. Transcriptome data are enriched by correlative analysis with the computed morphometric indices. Next, a subset of enriched data are processed against publicly available ChIP-Seq data using Model-based Analysis of Regulation of Gene Expression to predict regulatory transcription factors. This integrative analysis of morphometric and transcriptomic data predicted YY1 as one of the cis-regulators in both cell lines as a result of the increased stiffness of the microenvironment. Subsequent experiments validated that YY1 is expressed at protein and mRNA levels for MCF10A and 184A1, respectively. Also, there is a causal relationship between activation of YY1 and ERBB2 when YY1 is overexpressed at the protein level in MCF10A. Supplementary information Supplementary data are available at Bioinformatics online.

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