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Genome-wide analysis identifies aberrant methylation in Fragile X syndrome is specific to the FMR1 locus

ABSTRACT: Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is caused by an expansion of CGG repeats located in the 5Õ untranslated region (UTR) of the FMR1 gene, leading to hypermethylation and silencing of this locus. While the dramatic increase in DNA methylation (DNAm) of the FMR1 full mutation allele is well documented, the extent that these changes affect DNAm throughout the entire gene and the rest of the genome remains unexplored. Here, we examine the genome-wide methylation in peripheral blood (N = 9) as well as induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls (N = 53 and 9, respectively) and find the expected significant DNAm differences in the FMR1 promoter and 5Õ UTR, but also that these changes inversely persist throughout the FMR1 gene body. Importantly, we find there are no additional differential methylated loci (DML) throughout the remainder of the genome, indicating that the aberrant methylation of the FMR1 in FXS is locus-specific and does not change DNAm genome-wide. This study provides a comprehensive methylation profile of FXS and refines mechanistic considerations of FMR1 silencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE41273 | GEO | 2013/04/15

SECONDARY ACCESSION(S): PRJNA176419

REPOSITORIES: GEO

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Genome-wide analysis identifies aberrant methylation in Fragile X syndrome is specific to the FMR1 locus

Project description:Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is caused by an expansion of CGG repeats located in the 5Õ untranslated region (UTR) of the FMR1 gene, leading to hypermethylation and silencing of this locus. While the dramatic increase in DNA methylation (DNAm) of the FMR1 full mutation allele is well documented, the extent that these changes affect DNAm throughout the entire gene and the rest of the genome remains unexplored. Here, we examine the genome-wide methylation in peripheral blood (N = 9) as well as induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls (N = 53 and 9, respectively) and find the expected significant DNAm differences in the FMR1 promoter and 5Õ UTR, but also that these changes inversely persist throughout the FMR1 gene body. Importantly, we find there are no additional differential methylated loci (DML) throughout the remainder of the genome, indicating that the aberrant methylation of the FMR1 in FXS is locus-specific and does not change DNAm genome-wide. This study provides a comprehensive methylation profile of FXS and refines mechanistic considerations of FMR1 silencing. A total of 62 blood (53 controls + 9 Fragile X) samples analyzed using a linear regression model.

2013-04-15 | E-GEOD-41273 | biostudies-arrayexpress

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Project description:The primary mechanism causing Fragile X syndrome (FXS) is the expansion and silencing of a repetitive CGG sequence in the 5’-UTR of the FMR1 gene. Previous work has demonstrated that chemical disruption of DNA methylation induces FMR1 expression in FXS-iPSCs. To further explore the maintenance of DNA methylation in the FMR1 locus, and to test the possibility of FMR1 reactivation using gene targeting of a single epigenetic factor, we performed a global transcriptional analysis of FXS-iPSCs infected with a lentiviral construct containing Cas9 and sgRNA targeting DNMT1.

2022-06-01 | GSE182391 | GEO

Rescue of Fragile X syndrome by DNA methylation editing of the FMR1 [ChIP-seq II]

Project description:Fragile X syndrome (FXS), the most common genetic form of intellectual disability in male, is caused by the silence of FMR1. Hypermethylation of the CGG expansion mutation in the 5’UTR region of FMR1 in FXS patients was thought to epigenetically silence FMR1. Here, we applied our previously developed DNA methylation editing tool to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/gRNA switched the heterochromatin status of the FMR1 promoter to an active chromatin status and subsequently restored FMR1 expression in FXS iPSCs. Neurons derived from methylation edited FXS iPSCs showed a similar electrophysiological property as wild-type neurons, and maintained FMR1 expression for months after engrafting into the mouse brain. Reactivation of FMR1 can be achieved in FXS neurons with demethylation of the CGG expansion. Lastly, we showed that targeted demethylation of the FMR1 promoter can reactivate FMR1 as well suggesting potential therapeutic approaches for FXS.

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Rescue of Fragile X syndrome by DNA methylation editing of the FMR1 [ChIP-seq]

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DNAseq analysis of a genome-wide loss-of-function CRISPR/Cas9 library in haploid human embryonic stem cells transfected with a methylated construct containing the FXS-related mutation upstream to an EGFP reporter gene

Project description:The primary mechanism causing Fragile X syndrome (FXS) is the expansion and silencing of a repetitive CGG sequence in the 5’-UTR of the FMR1 gene. To identify novel epigenetic pathways involved in FXS pathogenesis, we have established a model system for FMR1 silencing using a construct containing the FXS-related FMR1 CGG expansion upstream to an EGFP reporter gene. This construct was methylated in vitro and introduced into a genome-wide loss-of-function (LOF) library established in haploid human pluripotent stem cells. Library cells were then sorted to GFP-positive and GFP-negative populations. The analysis of the changes in abundance of mutants between the GFP-positive and GFP-negative populations has yielded a list of candidate genes whose functional loss reversed the methylation-induced silencing of the expanded FMR1 5'-UTR sequence.

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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

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

2018-02-16 | GSE108171 | GEO

Antisense Oligonucleotide Rescue of CGG Expansion-Dependent FMR1 Mis-Splicing in Fragile X Syndrome Restores FMRP

Project description:Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissue of individuals with fragile X syndrome (FXS). Surprisingly, the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene is transcribed in >70% of the FXS tissues. In all FMR1 expressing FXS tissues, FMR1 RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known FMR1-217 RNA isoform, which is comprised of FMR1 exon 1 and a pseudo-exon in intron 1. FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissue. We show that in cells aberrantly expressing mis-spliced FMR1, antisense oligonucleotide (ASO) treatment reduces FMR1-217, rescues full-length FMR1 RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, FMR1 gene reactivation in transcriptionally silent FXS cells using 5-aza-2′-deoxycytidine (5-AzadC), which prevents DNA methylation, increases FMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length FMR1 expression and restores FMRP. These findings indicate that mis-regulated RNA processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing FMR1-217, ASO treatment may offer a new therapeutic approach to mitigate the disorder.

2023-06-14 | GSE202178 | GEO

Antisense Oligonucleotide Rescue of CGG Expansion-Dependent FMR1 Mis-Splicing in Fragile X Syndrome Restores FMRP

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Targeted reactivation of FMR1 transcription in FXS embryonic stem cells

Project description:The aim of this work is to selectively increase transcription from the FMR1 locus in FXS hESC lines using CRISPR-Cas9 fused to transcriptional activators.

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