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NIH Research Festival

September 23 – 25, 2024

The role of MSH2 in CGG repeat stability and methylation at the FMR1 locus in Fragile X Syndrome

Authors

  • J Grant-Bier
  • K Ruppert
  • B Hayward
  • K Usdin
  • D Kumari

Abstract

Fragile X Syndrome (FXS) is the most common form of heritable intellectual disability caused by expansion of a CGG-repeat tract in the 5’ untranslated region of the FMR1 gene to >200 repeats. This induces DNA hypermethylation and results in transcriptional silencing. Repeat induced epigenetic changes are also seen in other repeat expansion diseases (REDs), but the underlying mechanism is unknown. MSH2, a protein involved in mismatch repair, is important for maintaining DNA methylation at the DMPK locus in myotonic dystrophy type 1 (DM1), an RED caused by CTG-repeat expansion. Here we studied MSH2’s role in DNA methylation in the FMR1 promoter region in FXS and in the region upstream of the expanded GAA repeats in the intron 1 of the frataxin (FXN) gene in Friedreich’s ataxia (FRDA). CRISPR knockout (KO) of MSH2 in FXS embryonic stem cells (ESCs) and FRDA induced pluripotent stem cells did not decrease DNA methylation in either the FMR1 or the FXN gene, suggesting that MSH2 is not necessary for the maintenance of DNA methylation in these disorders. To study MSH2’s role in de novo methylation in FXS, we used transient transfection of dCas9-Tet1 with CGG gRNA to demethylate the FMR1 promoter. The FMR1 gene was demethylated and reactivated in FXS ESCs with and without MSH2 and showed extensive CGG repeat contractions to below the methylation threshold. While this precludes the use of this system to study MSH2’s role in de novo methylation, understanding the contraction mechanisms will improve our understanding of repeat instability in REDs.

Scientific Focus Area: Molecular Biology and Biochemistry

This page was last updated on Tuesday, August 6, 2024

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Current Research Festival

  • 2025
  • 2024
    • General Schedule of Events
    • 2024 NIH Distinguished Scholars Program
    • Poster Sessions
    • Concurrent Workshops
    • NIH Resource Information Fair
    • National Academy of Science Mini-Symposium
    • Special Wednesday Events
    • Vendor Exhibit Information
    • Green Labs Fair
    • Research Festival Committee
  • 2023
    • General Schedule of Events
    • NIH Early–Career Investigator Lectures
    • Poster Sessions
    • Concurrent Workshops
    • NIH Resource Information Fair
    • Vendor Exhibit Information
    • Research Festival Committee
  • 2021
  • 2019
    • General Schedule of Events
    • Plenary Sessions
    • Poster Session
    • Data Blitz
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    • Special Exhibits on Resources for Intramural Research
    • Technical Sales Association (TSA) Research Festival Exhibit Tent Show
    • Research Festival Committee
  • 2018
    • General Schedule of Events
    • Plenary Sessions
    • Concurrent Symposia Sessions
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    • Special Exhibits on Resources for Intramural Research
    • Technical Sales Association (TSA) Research Festival Exhibit Tent Show
    • Research Festival Committees
  • 2017
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    • Plenary Sessions
    • Concurrent Symposia Sessions
    • Poster Sessions
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    • Future Research Leaders
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  • 2016
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    • Plenary Sessions
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    • Browse by Presenter Name
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