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Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes [FXTAS]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48873 | GEO | 2014/02/20

SECONDARY ACCESSION(S): PRJNA212067

REPOSITORIES: GEO

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Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes [FXTAS]

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

Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes [SHSY5Y]

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

Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes [SHSY5Y]

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

The 3’UTR of FMR1 mRNA is a target of miR101, miR129-5p and miR-221: implications for the molecular pathology of FXTAS at the synapse.

Project description:While FMR1 is silenced in Fragile X syndrome (FXS), its expression is elevated (2-8 fold) in premutated individuals. These people may develop the Fragile X-associated Tremor Ataxia Syndrome (FXTAS), a late onset neurodegenerative disorder characterized by ataxia and parkinsonism. In addition, people carrying the premutation can be affected by a set of neurological and behavioural disorders during young age. Problems of memory have been detected in these patients as well in the mice model for FXTAS. To date little is known concerning the metabolism of FMR1 mRNA, notwithstanding the importance of the finely tuned regulation of the expression of this gene. In the present study we identified three microRNAs that specifically target the 3’UTR of FMR1 and can modulate its expression throughout the brain and, in particular, at the synaptic level. The expression level of miR-221 is reduced in brain and synaptosomal preparations of young FXTAS mice suggesting a general deregulation of transcripts located at the synapse of these mice. By transcriptome analysis we show here a robust deregulation of the expression levels of genes involved in learning, memory and autistic behavior, Parkinson disease and neurodegeneration. Interestingly, many of those deregulated mRNAs are target of the same miRNAs that modulate the expression of FMR1 at the synapse. Knock-In versus Wild Type, 3 replicates.

2013-03-07 | E-GEOD-43670 | biostudies-arrayexpress

The 3’UTR of FMR1 mRNA is a target of miR101, miR129-5p and miR-221: implications for the molecular pathology of FXTAS at the synapse.

2013-03-07 | GSE43670 | GEO

Genome-wide alteration of 5-hydroxymethylcytosine in a mouse model of fragile X-associated tremor/ataxia syndrome

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

CGG repeat RNA binding protein capture identifies SRSF protein kinase 1 as a modulator of RAN translation and suppressor of repeat toxicity

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

miRNA profiling of plasma from FMR1 premutation carriers

Project description:Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, life span. In particular, the expansions of the CGG-repeats stretch at the 5'-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. We profiled the miRNAs content of plasma from premutation carriers and controls. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers

2021-08-31 | GSE181018 | GEO

Knockdown and Overexpression of FMR4 in HEK293T cells at 6 and 24 hours

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

Rescue of Fragile X syndrome neurons by DNA methylation editing of the FMR1 gene [RNA-seq]

Project description:Fragile X syndrome (FXS), the most common genetic form of intellectual disability in male, is caused by silencing of the FMR1 gene by hypermethylation of the CGG expansion mutation in the 5’UTR region of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/sgRNA switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state restoring a persistent expression of FMR1 in FXS iPSCs. Neurons derived from methylation edited FXS iPSCs rescued the electrophysiological abnormalities and restored a wild-type phenotype upon the mutant neurons. FMR1 expression in edited neurons was maintained in vivo after engrafting into the mouse brain. Finally, demethylation of the CGG repeats in post-mitotic FXS neurons also reactivated FMR1. Our data establish demethylation of the CGG expansion is sufficient for FMR1 reactivation, suggesting potential therapeutic strategies for FXS.

2018-02-16 | GSE108498 | GEO

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