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WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome [RNA-seq]

ABSTRACT: Werner Syndrome (WS) is an autosomal recessive disorder characterized by premature aging due to mutations of the WRN gene. A classical sign in WS patients is short stature, but the underlying mechanisms are not well understood. Here we report that WRN is indispensable for chondrogenesis, which is the engine driving the elongation of bones and determines height.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206213 | GEO | 2022/07/28

REPOSITORIES: GEO

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WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome [ChIP-seq]

Project description:Werner Syndrome (WS) is an autosomal recessive disorder characterized by premature aging due to mutations of the WRN gene. A classical sign in WS patients is short stature, but the underlying mechanisms are not well understood. Here we report that WRN is indispensable for chondrogenesis, which is the engine driving the elongation of bones and determines height.

2022-07-28 | GSE206210 | GEO

WRN loss accelerates abnormal adipocyte metabolism in Werner Syndrome

Project description:Metabolic dysfunction is one of the main symptoms of Werner syndrome (WS); however, the underlying mechanisms remain unclear. Here, we report that loss of WRN accelerates adipogenesis at an early stage both in vitro (stem cells) and in vivo (zebrafish). Moreover, WRN depletion causes a transient upregulation of late-stage of adipocyte-specific genes at an early stage.

2024-01-26 | GSE248012 | GEO

Werner syndrome WRN helicase alters gene expression in a G-quadruplex DNA-dependent manner to antagonize a pro-senescence gene expression program

Project description:Werner syndrome (WS) is a human adult progeroid syndrome caused by loss-of-function mutations in the WRN RECQ helicase gene. We analyzed mRNA and miRNA expression in fibroblasts from WS patients and in fibroblasts depleted of WRN protein in order to determine the role of WRN in transcription regulation, and to identify genes and miRNAs that might drive WS disease pathogenesis. Genes altered in WS cells participate in cellular growth, proliferation and survival; in tRNA charging and in oncogenic signaling; and in connective tissue and developmental networks. Genes down-regulated in WS cells were highly enriched in Gquadruplex (G4) DNA motifs, indicating G4 motifs are physiologic substrates for WRN. In contrast, there was a remarkable, coordinate up-regulation of nearly all of the cytoplasmic tRNA synthetases and of genes associated with the senescence-associated secretory phenotype (SASP). These results identify canonical pathways that may drive the pathogenesis of Werner syndrome and associated disease risks.

2017-08-23 | GSE62877 | GEO

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Project description:Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in C. elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WRN syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

2020-01-13 | PXD015644 | Pride

Next Generation Mendelian Genetics: Atypical Werner Syndrome

Project description:Werner syndrome (WS) is an adult-onset progeroid syndrome characterized by accelerated aging. The International Registry of Werner Syndrome in the Department of Pathology, University of Washington, collects WS cases from all over the world. Classical WS is caused by WRN mutations. Those who do not carry WRN are categorized as "atypical Werner syndrome." A small subset of atypical WS is caused by LMNA mutations. There also are many cases whose causes are still unknown. The purpose of this study is to identify other causative gene(s) of atypical WS.

| phs000434.v1.p1 | EGA

NAD+ repletion inhibits accelerated aging in Werner syndrome through the restoration of mitophagy

Project description:Metabolic dysfunction is a primary feature of the premature aging Werner syndrome (WS), a heritable human disease caused by mutations in the gene encoding the DNA helicase Werner (WRN). However, the relationship between WRN mutation and its severe metabolic phenotypes is unclear. Here we report mitochondrial dysfunction and depletion of NAD+, a fundamental ubiquitous cofactor, in WS patient samples and WS animal models. NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably delays accelerated aging, including stem cell dysfunction in both C. elegans and Drosophila models of WS. Mechanistically, WRN physically binds to a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) and facilitates its NAD+ production. Our findings reveal an unprecedented anti-aging mechanism of WRN that integrates its new function of NAD+ synthesis to coordinate mitochondrial maintenance and energy expenditure, and suggest therapeutic potential.

2019-08-16 | GSE108968 | GEO

Expression data from Werner syndrome iPSCs

Project description:Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. We used microarrays to examine whether global gene expression profile of WS iPSCs is similar to that of normal iPSCs and human ESCs, as well as premature senescence phenotype is suppressed by reprogramming.

2014-12-31 | GSE62114 | GEO

Pathogenic de novo variant in WRN induces exon skipping and underlies Werner Syndrome

Project description:Werner Syndrome, an autosomal recessive disorder associated with premature aging, results from mutations in the WRN gene. Patients exhibit susceptibility to tumors and pathological changes, including eye alterations, skin lesions, and hair thinning, along with complications such as diabetes, osteoporosis, and tumors. This study investigates the genetic basis of a Chinese patient clinically diagnosed with presumed Werner syndrome and partial lipoatrophic diabetes mellitus.High-throughput sequencing of genomic DNA from a blood sample was conducted. Confirmation of the identified homozygous variant (WRN_intron9 c.1270-1G>C) involved the construction of a mutant overexpression vector, primer design, PCR amplification, and sequencing. In silico predictions and structural modeling assessed the variant's pathogenicity, while cell function assays validated the induced phenotype.The study identifies a novel WRN variant as a potential pathogenic factor in the patient. This variant co-segregated with the disease in the pedigree. Database searches (Human Gene Mutation Database, Leiden Open Variant Database, UMD-DMD) revealed its novelty. Simulation predicts exon 10 tandem repeat escape due to the WRN_intron9 c.1270-1G>C mutation. Cellular assays confirm senescent phenotype induction and progerin accumulation, leading to premature cellular senescence.The study reports the identification of a novel WRN variant, likely the pathogenic basis for Werner Syndrome in the Chinese patient. Notably, this marks the first report of a homozygous WRN variant in Werner Syndrome.

2024-08-05 | GSE269189 | GEO

Gene expression profiling in the liver of 3-month old mice with a mutant Wrn protein treated with vitamin C compared to the liver of 3-month old untreated mice with a mutant Wrn protein.

Project description:Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. We generated a mouse model with a deletion in the helicase domain of the murine WRN homologue that recapitulates most of the WS phenotypes including an abnormal hyaluronic acid excretion, higher reactive oxygen species (ROS) levels, increased genomic instability and cancer incidence resulting in a 10-15% decreased life span expectancy. In addition, WS patients and Wrn mutant mice show hallmarks of a metabolic syndrome including premature visceral obesity, hypertriglyceridemia, insulin-resistant diabetes type 2 and associated cardiovascular diseases. In this study, we compared the expression profile of liver tissues from 3 months old Wrn mutant mice treated with 0.4% vitamin C to untreated 3 months old Wrn mutant mice.

2015-05-09 | GSE68688 | GEO

Gene expression profiling in the liver of 3-month old mice with a mutant Wrn protein treated with vitamin C compared to the liver of 3-month old untreated mice with a mutant Wrn protein.

2015-05-09 | E-GEOD-68688 | biostudies-arrayexpress