Evidence map›Paper›PMID 40296143›Full record

ArticleEpigenetics & chromatin2025

MSH2 is not required for either maintenance of DNA methylation or repeat contraction at the FMR1 locus in fragile X syndrome or the FXN locus in Friedreich's ataxia.

Jessalyn Grant-Bier, Kathryn Ruppert, Bruce Hayward, Karen Usdin, Daman Kumari

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Article in Epigenetics & chromatin, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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5 · Who and what money

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5 authors.

Jessalyn Grant-Bier *Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Kathryn Ruppert *Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Bruce HaywardSection on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Karen UsdinSection on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Daman KumariSection on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. damank@nih.gov.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundRepeat-induced epigenetic changes are observed in many repeat expansion disorders (REDs). These changes result in transcriptional deficits and/or silencing of the associated gene. MSH2, a mismatch repair protein that is required for repeat expansion in the REDs, has been implicated in the maintenance of DNA methylation seen in the region upstream of the expanded CTG repeats at the DMPK locus in myotonic dystrophy type 1 (DM1). Here, we investigated the role of MSH2 in aberrant DNA methylation in two additional REDs, fragile X syndrome (FXS) that is caused by a CGG repeat expansion in the 5' untranslated region (UTR) of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, and Friedreich's ataxia (FRDA) that is caused by a GAA repeat expansion in intron 1 of the frataxin (FXN) gene.

resultsIn contrast to what is seen at the DMPK locus in DM1, loss of MSH2 did not decrease DNA methylation at the FMR1 promoter in FXS embryonic stem cells (ESCs) or increase FMR1 transcription. This difference was not due to the differences in the CpG density of the two loci as a decrease in DNA methylation was also not observed in a less CpG dense region upstream of the expanded GAA repeats in the FXN gene in MSH2 null induced pluripotent stem cells (iPSCs) derived from FRDA patient fibroblasts. Surprisingly, given previous reports, we found that FMR1 reactivation was associated with a high frequency of MSH2-independent CGG-repeat contractions that resulted a permanent loss of DNA methylation. MSH2-independent GAA-repeat contractions were also seen in FRDA cells.

conclusionsOur results suggest that there are mechanistic differences in the way that DNA methylation is maintained in the region upstream of expanded repeats among different REDs even though they share a similar mechanism of repeat expansion. The high frequency of transcription-induced MSH2-dependent and MSH2-independent contractions we have observed may contribute to the mosaicism that is frequently seen in carriers of FMR1 alleles with expanded CGG-repeat tracts. These contractions may reflect the underlying problems associated with transcription through the repeat. Given the recent interest in the therapeutic use of transcription-driven repeat contractions, our data may have interesting mechanistic, prognostic, and therapeutic implications.

Indexed as

DNA MethylationFragile X Messenger Ribonucleoprotein 1Fragile X SyndromeFriedreich AtaxiaIron-Binding ProteinsMutS Homolog 2 ProteinFrataxinHumansTrinucleotide Repeat ExpansionFMR1 protein, humanFragile X Messenger Ribonucleoprotein 1FrataxinIron-Binding ProteinsMSH2 protein, humanMutS Homolog 2 ProteinDNA damageDNA methylationFragile X syndromeFriedreich’s ataxiaMismatch repairMSH2Repeat expansion

Identifiers

PMID40296143
PMCPMC12036138

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