scholarly journals Loss of function of the RNA export factor, Nxt1, in Drosophila causes muscle degeneration and reduced expression of genes with long introns

2019 ◽  
Author(s):  
Kevin van der Graaf ◽  
Helen White-Cooper
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Mrna Export ◽  
Circular Rnas ◽  
Specific Gene ◽  
Muscle Degeneration ◽  
Loss Of Function ◽  
Export Pathway ◽  
Expression Of Genes ◽  
Rna Export

AbstractThe RNA export pathway is essential for export-competent mRNAs to pass from the nucleus into the cytoplasm, and thus is essential for protein production and normal function of cells. Drosophila with partial loss of function of Nxt1, a core factor in the pathway, show reduced viability and male and female sterility. The male sterility has previously been shown to be caused by defects in testis-specific gene expression, particularly of genes without introns. Here we describe a specific defect in growth and maintenance of the larval muscles, leading to muscle degeneration in Nxt1 mutants. RNAseq revealed reduced expression of mRNAs of many genes in Nxt1 mutant muscles. Despite this, the degeneration was rescued by increased expression of a single gene, the costamere component tn (abba), in muscles. Genes under-expressed in the mutant typically have long introns, and most normally encode circular RNAs in addition to mRNAs. This is the first report of a specific role for the RNA export pathway gene Nxt1 in muscle integrity. Our data on Nxt1 links the mRNA export pathway to a global role in mRNA expression of genes that also produce circular RNAs, in vivo.Author summaryIn eukaryotic cells the DNA encoding instructions for protein synthesis is located in the nucleus, it is transcribed to generate pre-mRNA, which is processed at both ends and spliced to remove internal spacer regions (introns) to generate mRNA. This mRNA is then transported by the mRNA export pathway via nuclear pores to the cytoplasm for protein synthesis. We have previously shown that reduction in activity of a specific protein in the mRNA export pathway, Nxt1, has an additional role in testis-specific transcription. Here we describe a further role for this protein specifically in gene expression, particularly of genes with long introns, and in muscle maintenance. Drosophila larvae with reduced Nxt1 activity have normal muscle pattern when they are small, but show muscular atrophy and degeneration as they grow, resulting in significant defects in their movement speed. We discovered that expression of many genes is reduced in the mutant larvae, but that restoring the expression of just one of these, abba, the Drosophila homologue of Trim32 (a human gene involved in muscular dystrophy) is capable of preventing the muscle degeneration.

scholarly journals Roles for RNA export factor, Nxt1, in ensuring muscle integrity and normal RNA expression in Drosophila

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kevin van der Graaf ◽  
Katia Jindrich ◽  
Robert Mitchell ◽  
Helen White-Cooper
Keyword(s):  
Mrna Export ◽  
Rna Stability ◽  
Muscle Degeneration ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Partial Loss ◽  
Export Pathway ◽  
Pathway Gene ◽  
Rna Export

Abstract The mRNA export pathway is responsible for the transport of mRNAs from the nucleus to the cytoplasm, and thus is essential for protein production and normal cellular functions. A partial loss of function allele of the mRNA export factor Nxt1 in Drosophila shows reduced viability and sterility. A previous study has shown that the male fertility defect is due to a defect in transcription and RNA stability, indicating the potential for this pathway to be implicated in processes beyond the known mRNA transport function. Here we investigate the reduced viability of Nxt1 partial loss of function mutants, and describe a defect in growth and maintenance of the larval muscles, leading to muscle degeneration. RNA-seq revealed reduced expression of a set of mRNAs, particularly from genes with long introns in Nxt1 mutant carcass. We detected differential expression of circRNA, and significantly fewer distinct circRNAs expressed in the mutants. Despite the widespread defects in gene expression, muscle degeneration was rescued by increased expression of the costamere component tn (abba) in muscles. This is the first report of a role for the RNA export pathway gene Nxt1 in the maintenance of muscle integrity. Our data also links the mRNA export pathway to a specific role in the expression of mRNA and circRNA from common precursor genes, in vivo.

scholarly journals WRN modulates translation by influencing mRNA export from the nucleus through its interaction with the export receptor NXF1 in HeLa cancer cell

2020 ◽  
Author(s):  
Juan Manuel Iglesias-Pedraz ◽  
Diego Matia Fossatti Jara ◽  
Valeria Del Carmen Valle-Riestra Felice ◽  
Sergio Rafael Cruz Visalaya ◽  
Jose Antonio Ayala Felix ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Werner Syndrome ◽  
Mrna Export ◽  
Premature Aging ◽  
Metabolic Shift ◽  
Loss Of Function ◽  
Global Protein Synthesis

Abstract Background The Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation.Results To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN directly interacts with mRNA and the mRNA export receptor Nuclear Export Factor 1 (NXF1).Conclusions Our findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.

scholarly journals WRN modulates translation by influencing nuclear mRNA export in HeLa cancer cells

2020 ◽  
Author(s):  
Juan Manuel Iglesias-Pedraz ◽  
Diego Matia Fossatti Jara ◽  
Valeria Del Carmen Valle-Riestra Felice ◽  
Sergio Rafael Cruz Visalaya ◽  
Jose Antonio Ayala Felix ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Werner Syndrome ◽  
Mrna Export ◽  
Premature Aging ◽  
Metabolic Shift ◽  
Loss Of Function ◽  
Global Protein Synthesis

Abstract BackgroundThe Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation.ResultsTo identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN interacts with mRNA and the Nuclear RNA Export Factor 1 (NXF1).ConclusionsOur findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.

Gene Expression Profiling of Hyperdiploid Multiple Reveal Complex Gene Dosage Effects and an mRNA Translation/Protein Synthesis Signature.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1538-1538
Author(s):  
Wee-Joo Chng ◽  
Scott Van Wier ◽  
Gregory Ahmann ◽  
Tammy Price-Troska ◽  
Kim Henderson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Differentially Expressed Genes ◽  
Gene Dosage ◽  
Gene Copy Number ◽  
Mrna Translation ◽  
Differentially Expressed ◽  
Gene Copy ◽  
Gene Dosage Effect ◽  
Expression Of Genes

Abstract Hyperdiploid MM (H-MM), characterized by recurrent trisomies constitute about 50% of MM, yet very little is known about its pathogenesis and oncogenic mechanisms. Studies in leukemia and solid tumors have shown gene dosage effect of aneuploidy on gene expression. To determine the possible gene dosage effect and deregulated cellular program in H-MM we undertook a gene expression study of CD138-enriched plasma-cell RNA from 53 hyperdiploid and 37 non-hyperdiploid MM (NH-MM) patients using the Affymetrix U133A chip (Affymetrix, Santa Clara, CA). Gene expression data was analyzed using GeneSpring 7 (Agilent Technologies, Palo Alto, CA). Genes differentially expressed between H-MM and NH-MM were obtained by t-test (p<0.01). The majority of the differentially expressed genes (57%) were under-expressed in H-MM. Genes located on the commonly trisomic chromosomes were mostly (but not always) over-expressed in H-MM and constitute 76% of over-expressed genes. Chromosome 1 contained the most differentially expressed genes (17%) followed by chromosome 12 (9%), and 19 (8%). To examine the relationship of gene copy number to gene expression, we examined the expression of genes on chromosomes 9 and 15 in subjects with 2 copies (15 normal control and 20 NH-MM) and 3 copies (12 H-MM) of each chromosome as detected by interphase FISH. We then derived a ratio of the mean expression of each gene on these chromosomes between patients with 3 copies and 2 copies of the chromosome. If a simple relationship exists between gene expression and gene copy number, one would expect the ratio of expression of most genes on these two chromosomes to be about 1.5 in H-MM compared to NH-MM. However, many genes have ratios either higher than 2 or lower than 0.5. Furthermore, when the heterogeneity of cells with underlying trisomies is taken into consideration by correcting the ratio for the number of cells with trisomies, the actual ratio is always lower than the expected ratio. When the expression of genes on a chromosome was compressed to a median value, this value was always higher in the trisomic chromosomes for H-MM compared to NH-MM. The data suggests that although gene dosage influence gene expression, the relationship is complex and some genes are more gene dosage dependent than others. Amongst the differentially expressed genes with known function, 33% are involved in mRNA translation/protein synthesis. Of note, 37 of the top 100 differentially expressed genes are involved in these processes. In particular, 60 ribosomal protein (RP) genes are significantly (p<0.05) upregulated in H-MM. This signature in H-MM is not associated with increase proliferation as measured by PCLI. This predominant signature suggests that deregulated protein synthesis may be important for the biology of H-MM. Many of these RPs are involved in the synthesis of product of oncogenic pathways (e.g. MYC, NF-KB pathways) and may mediate the growth and survival of tumor cells. It is therefore possible that these tumor cells may be sensitive to the disruption of mRNA translation/protein synthesis. Targeting the mTOR pathway with rapamycin may therefore be useful for treatment of H-MM.

Epigenetic Effects of IDH1/IDH2 Mutations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-33-SCI-33 ◽  
Author(s):  
Ari M. Melnick ◽  
Ross L Levine ◽  
Maria E Figueroa ◽  
Craig B. Thompson ◽  
Omar Abdel-Wahab
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Malignant Transformation ◽  
Covalent Modification ◽  
Specific Gene ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Hematopoietic Stem

Abstract Abstract SCI-33 Epigenetic deregulation of gene expression through aberrant DNA methylation or histone modification plays an important role in the malignant transformation of hematopoietic cells. In particular, acute myeloid leukemias (AMLs) can be classified according to epigenetic signatures affecting DNA methylation or histone modifications affecting specific gene sets. Heterozygous somatic mutations in the loci encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in ∼20% of AMLs and are accompanied by global DNA hypermethylation and hypermethylation and silencing of a number of specific gene promoters. IDH1/2 mutations are almost completely mutually exclusive with somatic loss-of-function mutations in TET2, which hydroxylates methylcytosine (mCpG). DNA hydroxymethylation can function as an intermediate step in mCpG demethylation. TET2 mutant de novo AMLs also display global and promoter specific hypermethylation partially overlapping with IDH1/2 mutant cases. Mutations in the IDH1/2 loci result in a neomorphic enzyme that generates the aberrant oncometabolite 2-hydroxyglutarate (2HG) using α-ketoglutarate (αKG) as a substrate. 2HG can disrupt the activity of enzymes that use αKG as a cofactor, including TET2 and the jumonji family of histone demethylases. Expression of mutant IDH isoforms inhibits TET2 hydroxymethylation and jumonji histone demethylase functions. IDH and TET2 mutant AMLs accordingly exhibit reduced levels of hydroxymethylcytosine and a trend towards increased histone methylation. Mutant IDH or TET2 loss of function causes differentiation blockade and expansion of hematopoietic stem cells and TET2 knockout results in a myeloproliferative phenotype in mice. Hydroxymethylcytosine is in abundance in hematopoietic stem cells and displays specific distribution patterns, yet the function of this covalent modification is not fully understood. Recent data link TET2 with the function of cytosine deaminases as a pathway towards DNA demethylation, which has implications as well for B cell lymphomas and CML lymphoid blast crisis, which are linked with the actions of activation induced cytosine deaminase. Altogether, the available data implicate mutations in IDH1/2 and TET2 in promoting malignant transformation in several tissues, by disrupting epigenomics programming and altering gene expression patterning. Disclosures: Thompson: Agios Pharmaceuticals: Consultancy.

scholarly journals WRN modulates translation by influencing nuclear mRNA export in HeLa cancer cells

2020 ◽  
Author(s):  
Juan Manuel Iglesias-Pedraz ◽  
Diego Matia Fossatti Jara ◽  
Valeria Del Carmen Valle-Riestra Felice ◽  
Sergio Rafael Cruz Visalaya ◽  
Jose Antonio Ayala Felix ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Werner Syndrome ◽  
Mrna Export ◽  
Premature Aging ◽  
Metabolic Shift ◽  
Loss Of Function ◽  
Global Protein Synthesis

Abstract Background The Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation.Results To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN interacts with mRNA and the Nuclear RNA Export Factor 1 (NXF1).Conclusions Our findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.

scholarly journals PSVII-6 Effects of 25-hydroxycholecalciferol supplementation on gene expression of feedlot cattle

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 302-303
Author(s):  
Tainá E Martins ◽  
Tiago S Acedo ◽  
Vinicius N Gouvea ◽  
Guilherme S Vasconcellos ◽  
Mário B Arrigoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Growth Regulation ◽  
Block Design ◽  
Basal Diet ◽  
Feedlot Cattle ◽  
Finishing Cattle ◽  
Finishing Diets ◽  
Expression Of Genes ◽  
25 Hydroxycholecalciferol

Abstract The objective was to evaluate the effects of 25-hydroxycholecalciferol (HyD®, DSM Produtos Nutricionais Brasil S.A.) supplementation in expression of genes related to anabolism and catabolism of feedlot cattle. A total of 120 Nellore bulls (IBW = 370±20 kg) were distributed in 24 fully roofed-pens with concrete floor (5 animals/pen) in a randomized complete block design (8 pens/treatment). The treatments were T1 (control): no supplementation of HyD®; T2: HyD® supplementation at 1 mg/animal/day; T3: HyD® supplementation at 3 mg/animal/day. Basal diet was formulated to meet requirements of finishing bulls, considering an ADG of 1.6 kg/day (Level 2 Nutrition System, Fox et al., 2004). Adaptation to diets followed a step-up scheme for 14 days, with concentrate inclusion being gradually increased from 76 to 91% DM. Finishing diets were offered from 15th to 100th day of feedlot period and animals fed twice a day (0800 and 1500), with bunks managed for a maximum of 5% orts. After slaughter, muscle samples were collected for quantitative evaluation of gene expression using RT-qPCR method, considering the following genes: SOD1 (antioxidant marker), IGF1, IGF2 and MTOR (anabolism), FOXO1, MURF1, Atrogin-1 and MSTN (catabolism). Statistical analysis was performed using PROC MIXED of SAS® and means compared by Tukey test at 5% probability. No significant differences among treatments were observed for SOD1, FOXO1, MURF1 and Atrogin-1 expression (P >0.05). However, tendencies (0.05 > P ≤0.10) could be observed for IGF1, IGF2, MTOR and MSTN expression in animals receiving HyD®, regardless of dosage. These results indicate a positive effect of HyD® on muscular anabolism and protein synthesis on feedlot finishing cattle. Moreover, the greater expression on MSTN suggest a higher protein turnover and muscular growth regulation. In conclusion, HyD® supplementation increased expression of genes correlated to muscular growth and protein synthesis, being a viable technology for beef cattle finished in feedlot systems.

scholarly journals Varying intolerance of gene pathways to mutational classes explain genetic convergence across neuropsychiatric disorders

2016 ◽  
Author(s):  
Shahar Shohat ◽  
Eyal Ben-David ◽  
Sagiv Shifman
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
De Novo ◽  
Expression Patterns ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Brain Gene Expression

AbstractGenetic susceptibility to Intellectual disability (ID), autism spectrum disorder (ASD) and schizophrenia (SCZ) often arises from mutations in the same genes, suggesting that they share common mechanisms. We studied genes with de novo mutations in the three disorders and genes implicated by SCZ genome-wide association study (GWAS). Using biological annotations and brain gene expression, we show that mutation class explains enrichment patterns more than specific disorder. Genes with loss of function mutations and genes with missense mutations were enriched with different pathways, shared with genes intolerant to mutations. Specific gene expression patterns were found for each disorder. ID genes were preferentially expressed in fetal cortex, ASD genes also in fetal cerebellum and striatum, and genes associated with SCZ were most significantly enriched in adolescent cortex. Our study suggests that convergence across neuropsychiatric disorders stems from vulnerable pathways to genetic variations, but spatiotemporal activity of genes contributes to specific phenotypes.

scholarly journals Intronic enhancers regulate the expression of genes involved in tissue-specific functions and homeostasis

2020 ◽  
Author(s):  
Beatrice Borsari ◽  
Pablo Villegas-Mirón ◽  
Hafid Laayouni ◽  
Alba Segarra-Casas ◽  
Jaume Bertranpetit ◽  
...  
Keyword(s):  
Gene Expression ◽  
Embryonic Stem ◽  
Gene Expression Pattern ◽  
Specific Gene ◽  
Control Of Gene Expression ◽  
Tissue Specific ◽  
Tissue Specific Gene ◽  
Specific Gene Expression ◽  
Expression Of Genes ◽  
Genomic Location

AbstractTissue function and homeostasis reflect the gene expression signature by which the combination of ubiquitous and tissue-specific genes contribute to the tissue maintenance and stimuli-responsive function. Enhancers are central to control this tissue-specific gene expression pattern. Here, we explore the correlation between the genomic location of enhancers and their role in tissue-specific gene expression. We found that enhancers showing tissue-specific activity are highly enriched in intronic regions and regulate the expression of genes involved in tissue-specific functions, while housekeeping genes are more often controlled by intergenic enhancers. Notably, an intergenic-to-intronic active enhancers continuum is observed in the transition from developmental to adult stages: the most differentiated tissues present higher rates of intronic enhancers, while the lowest rates are observed in embryonic stem cells. Altogether, our results suggest that the genomic location of active enhancers is key for the tissue-specific control of gene expression.

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