{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T20:52:18Z","timestamp":1767991938478,"version":"3.49.0"},"reference-count":100,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Epigenetics &amp; Chromatin"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Repeat-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 <jats:italic>DMPK<\/jats:italic> 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\u2019 untranslated region (UTR) of the <jats:italic>Fragile X Messenger Ribonucleoprotein 1<\/jats:italic> (<jats:italic>FMR1<\/jats:italic>) gene, and Friedreich\u2019s ataxia (FRDA) that is caused by a GAA repeat expansion in intron 1 of the <jats:italic>frataxin<\/jats:italic> (<jats:italic>FXN<\/jats:italic>) gene.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In contrast to what is seen at the <jats:italic>DMPK<\/jats:italic> locus in DM1, loss of MSH2 did not decrease DNA methylation at the <jats:italic>FMR1<\/jats:italic> promoter in FXS embryonic stem cells (ESCs) or increase <jats:italic>FMR1<\/jats:italic> 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 <jats:italic>FXN<\/jats:italic> gene in MSH2 null induced pluripotent stem cells (iPSCs) derived from FRDA patient fibroblasts. Surprisingly, given previous reports, we found that <jats:italic>FMR1<\/jats:italic> 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our 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 <jats:italic>FMR1<\/jats:italic> 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1186\/s13072-025-00588-4","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T04:16:55Z","timestamp":1745813815000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["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\u2019s ataxia"],"prefix":"10.1186","volume":"18","author":[{"given":"Jessalyn","family":"Grant-Bier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Ruppert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Hayward","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Usdin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daman","family":"Kumari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"issue":"5","key":"588_CR1","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1016\/j.ajhg.2021.03.011","volume":"108","author":"C Depienne","year":"2021","unstructured":"Depienne C, Mandel JL. 30 Years of repeat expansion disorders: what have we learned and what are the remaining challenges? 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