{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T19:32:22Z","timestamp":1787340742784,"version":"build-2736575974"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":232,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004243","name":"Prinses Beatrix Spierfonds","doi-asserted-by":"publisher","award":["W.OR18-06"],"award-info":[{"award-number":["W.OR18-06"]}],"id":[{"id":"10.13039\/501100004243","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Myotonic dystrophy type 1 (DM1) is caused by (CUG)n-expanded DMPK transcripts that sequester the splicing factor MBNL1 in the nucleus, resulting in widespread splicing abnormalities. Although significant progress has been made in understanding DM1 pathogenesis, the contribution of DMPK transcript levels to disease severity, and the variability of these levels across cell types, tissues, and patients, remains poorly understood. To investigate this in a quantitative manner, we developed isogenic human immortalized myoblast models with inducible modulation of DMPK RNA levels using CRISPR activation (CRISPRa) and interference (CRISPRi) guided by synthetic sgRNAs. CRISPRa elevated DMPK RNA levels by more than three-fold, intensifying MBNL1-dependent splicing defects. In contrast, CRISPRi reduced DMPK RNA expression by approximately 80%, partially rescuing splicing abnormalities. These changes were validated by visualizing (CUG)n foci using RNA FISH. Lowering DMPK transcript levels increased the availability of free nucleoplasmic MBNL1, whereas upregulation further depleted MBNL1, reinforcing the central role of MBNL1 sequestration in repeat RNA toxicity. Our findings demonstrate that expanded DMPK transcript levels modulate free MBNL1 concentration and alternative splicing in a dose-dependent manner, underscoring the central role of repeat RNA expression in DM1 pathogenesis. These models provide a powerful platform for dissecting variability in DMPK expression and for defining the therapeutic thresholds required for effective DMPK knockdown, thereby offering critical insights for the design and evaluation of DMPK and MBNL1-directed therapeutic strategies.<\/jats:p>","DOI":"10.1093\/hmg\/ddag079","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:44:55Z","timestamp":1785843895000},"source":"Crossref","is-referenced-by-count":0,"title":["CRISPR\/dCas9-mediated tuning of\n                    <i>DMPK<\/i>\n                    transcription reveals a quantitative relationship between toxic repeat RNA expression and MBNL1 activity in myotonic dystrophy"],"prefix":"10.1093","volume":"35","author":[{"given":"Lise","family":"Ripken","sequence":"first","affiliation":[{"name":"Radboud University Medical Center , Radboud Institute for Medical Innovation, Department of Medical BioSciences, 6525 GA, Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D","family":"Hoekman","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center , Radboud Institute for Medical Innovation, Department of Medical BioSciences, 6525 GA, Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke","family":"Willemse","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center , Radboud Institute for Medical Innovation, Department of Medical BioSciences, 6525 GA, Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maeve L","family":"Troost","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center , Radboud Institute for Medical Innovation, Department of Medical BioSciences, 6525 GA, Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique N","family":"Kenyon","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center , Radboud Institute for Medical Innovation, Department of Medical BioSciences, 6525 GA, Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walther J A A","family":"van den Broek","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center , Radboud Institute for Medical Innovation, Department of Medical BioSciences, 6525 GA, Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6773-8662","authenticated-orcid":false,"given":"Derick G","family":"Wansink","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center , Radboud Institute for Medical Innovation, Department of Medical BioSciences, 6525 GA, Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2026082114455896000_ref1","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/355548a0","article-title":"Cloning of the essential myotonic dystrophy region and mapping of the putative defect","volume":"355","author":"Aslanidis","year":"1992","journal-title":"Nature"},{"key":"2026082114455896000_ref2","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/0092-8674(92)90154-5","article-title":"Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member","volume":"68","author":"Brook","year":"1992","journal-title":"Cell"},{"key":"2026082114455896000_ref3","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1126\/science.1546325","article-title":"Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene","volume":"255","author":"Mahadevan","year":"1992","journal-title":"Science"},{"key":"2026082114455896000_ref4","doi-asserted-by":"publisher","first-page":"2674","DOI":"10.1212\/WNL.43.12.2674","article-title":"Somatic instability of CTG repeat in myotonic dystrophy","volume":"43","author":"Ashizawa","year":"1993","journal-title":"Neurology"},{"key":"2026082114455896000_ref5","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1093\/hmg\/ddac231","article-title":"Individual-specific levels of CTG\u2022CAG somatic instability are shared across multiple tissues in myotonic dystrophy type 1","volume":"32","author":"Morales","year":"2023","journal-title":"Hum. 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