MiRNA profiling of plasma from FMR1 premutation carriers
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE181018 | GEO | 2021/08/31
REPOSITORIES: GEO
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Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5M-bM-^@M-^Y-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5M-bM-^@M-^Y-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF. In the study presented here, we have 5 control samples plus one biological replicate and 9 patients with CGG expansions in the 5'UTR of the FMR1 gene (being premutation carriers)
2014-02-20 | E-GEOD-48873 | biostudies-arrayexpress
Project description:Transcribed CGG repeat expansions cause the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA-binding proteins (RBPs) into nuclear foci and undergo repeat-associated non-AUG (RAN) translation into toxic peptides in the cytoplasm. To identify proteins involved in these processes, we employed a CGG repeat RNA-tagging system to capture repeat associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine-rich domain) proteins that interact selectively with CGG repeats basally and under cellular stress. These same proteins modify toxicity in a Drosophila model of FXTAS. Genetic or pharmacological targeting of serine/arginine protein kinases (SRPKs) inhibits RAN translation in cells and toxicity in both FXTAS and C9orf72 ALS/FTD model flies. Furthermore, SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. These findings demonstrate roles for CGG repeat RNA binding proteins in repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders.
2021-09-28 | PXD027000 | Pride
Project description:Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder in which patients carry premutation alleles of 55-200 CGG repeats on the FMR1 gene. To date, whether alterations in epigenetic regulation modulate FXTAS has gone unexplored. 5-hydroxymethylcytosine (5hmC) converted from 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of proteins, has been found recently to play key roles in neuronal functions. Here we undertook genome-wide profiling of cerebellar 5hmC in a FXTAS mouse model (rCGG mice) and found that rCGG mice at 16 weeks showed overall reduced 5hmC levels genome-wide compared to age-matched wild-type littermates. However, we also observed gain-of-5hmC regions in repetitive elements, as well as cerebellum-specific enhancers, but not general enhancers. Genomic annotation and motif prediction of wild-type- and rCGG-specific differential 5-hydroxymethylated regions (DhMRs) revealed their high correlation with genes and transcription factors that are important in neuronal developmental and functional pathways. DhMR-associated genes partially overlapped with genes that were differentially associated with ribosomes in CGG mice identified by bacTRAP ribosomal profiling. Taken together, our data strongly indicate a functional role for 5hmC-mediated epigenetic modulation in the etiology of FXTAS, possibly through the regulation of transcription. Examination genome-wide 5hmC in FXTAS mice model
2013-10-17 | E-GEOD-49463 | biostudies-arrayexpress
Project description:CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism (Fragile X Syndrome, FXS), or adult-onset neurodegeneration (Fragile X-associated Tremor/Ataxia Syndrome, FXTAS). However, the FMR1 locus is complex and encodes several long noncoding RNAs (lncRNAs), whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. “Full”-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, and further investigated their function related to human neural precursor cells. We therefore propose that FMR4’s function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions. Study design includes 2 timepoints (6 and 24 hrs post-transfection) x 4 conditions (knockdown & control, overexpression & control) x 3 biological replicates. 3 technical replicates were pooled to creat each biological replicate.
2015-09-01 | E-GEOD-70817 | biostudies-arrayexpress
Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5M-bM-^@M-^Y-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5M-bM-^@M-^Y-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF. In the study presented here, we have 6 biological replicats for the Mock conditions, 6 biological replicates for the expression of the wild type FMR1 5'UTR, 6 biological replicates for the expression of the mutant FMR1 5'UTR and 6 biological replicates for the overexpression of the muatnt FMR1 5'UTR.
2014-02-20 | E-GEOD-48902 | biostudies-arrayexpress
Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5’-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5’-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF.
2014-02-20 | GSE48902 | GEO
Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5’-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5’-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF.
2014-02-20 | GSE48873 | GEO
Project description:Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder in which patients carry premutation alleles of 55-200 CGG repeats on the FMR1 gene. To date, whether alterations in epigenetic regulation modulate FXTAS has gone unexplored. 5-hydroxymethylcytosine (5hmC) converted from 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of proteins, has been found recently to play key roles in neuronal functions. Here we undertook genome-wide profiling of cerebellar 5hmC in a FXTAS mouse model (rCGG mice) and found that rCGG mice at 16 weeks showed overall reduced 5hmC levels genome-wide compared to age-matched wild-type littermates. However, we also observed gain-of-5hmC regions in repetitive elements, as well as cerebellum-specific enhancers, but not general enhancers. Genomic annotation and motif prediction of wild-type- and rCGG-specific differential 5-hydroxymethylated regions (DhMRs) revealed their high correlation with genes and transcription factors that are important in neuronal developmental and functional pathways. DhMR-associated genes partially overlapped with genes that were differentially associated with ribosomes in CGG mice identified by bacTRAP ribosomal profiling. Taken together, our data strongly indicate a functional role for 5hmC-mediated epigenetic modulation in the etiology of FXTAS, possibly through the regulation of transcription.
2013-10-17 | GSE49463 | GEO
Project description:CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism (Fragile X Syndrome, FXS), or adult-onset neurodegeneration (Fragile X-associated Tremor/Ataxia Syndrome, FXTAS). However, the FMR1 locus is complex and encodes several long noncoding RNAs (lncRNAs), whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. “Full”-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, and further investigated their function related to human neural precursor cells. We therefore propose that FMR4’s function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.
2015-09-01 | GSE70817 | GEO
Project description:Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associ-ated with the FMR1 premutation. Currently, it is not possible to determine when, and if, individ-ual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated path-ways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) overtime (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG re-peat allele size by Southern Blot and PCR analysis. The proteomic profile was obtained by Liquid Chromatography Mass Spectrometry (LC-MS/MS). We identified several significantly differenti-ated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways in-volved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered, and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and identification of unique biomarkers and dysregulated protein pathways of FXTAS
2023-08-17 | MSV000092680 | MassIVE