{"PubmedArticle":{"MedlineCitation":{"@attributes":{"Status":"MEDLINE","Owner":"NLM","IndexingMethod":"Curated"},"PMID":{"@attributes":{"Version":"1"},"@text":"39939773"},"DateCompleted":{"Year":"2025","Month":"05","Day":"07"},"DateRevised":{"Year":"2026","Month":"04","Day":"13"},"Article":{"@attributes":{"PubModel":"Print-Electronic"},"Journal":{"ISSN":{"@attributes":{"IssnType":"Electronic"},"@text":"1476-4687"},"JournalIssue":{"@attributes":{"CitedMedium":"Internet"},"Volume":"639","Issue":"8054","PubDate":{"Year":"2025","Month":"Mar"}},"Title":"Nature","ISOAbbreviation":"Nature"},"ArticleTitle":"Transcriptional adaptation upregulates utrophin in Duchenne muscular dystrophy.","Pagination":{"StartPage":"493","EndPage":"502","MedlinePgn":"493-502"},"ELocationID":[{"@attributes":{"EIdType":"doi","ValidYN":"Y"},"@text":"10.1038\/s41586-024-08539-x"}],"Abstract":{"AbstractText":["Duchenne muscular dystrophy (DMD) is a muscle-degenerating disease caused by mutations in the DMD gene, which encodes the dystrophin protein<sup>1,2<\/sup>. Utrophin (UTRN), the genetic and functional paralogue of DMD, is upregulated in some DMD patients<sup>3-5<\/sup>. To further investigate this UTRN upregulation, we first developed an inducible messenger RNA (mRNA) degradation system for DMD by introducing a premature termination codon (PTC) in one of its alternatively spliced exons. Inclusion of the PTC-containing exon triggers DMD mutant mRNA decay and UTRN upregulation. Notably, blocking nonsense-mediated mRNA decay results in the reversal of UTRN upregulation, whereas overexpressing DMD does not. Furthermore, overexpressing DMD<sup>PTC<\/sup> minigenes in wild-type cells causes UTRN upregulation, as does a wild-type DMD minigene containing a self-cleaving ribozyme. To place these findings in a therapeutic context, we used splice-switching antisense oligonucleotides (ASOs) to induce the skipping of out-of-frame exons of DMD, aiming to introduce PTCs. We found that these ASOs cause UTRN upregulation. In addition, when using an ASO to restore the DMD reading frame in myotubes derived from a DMD<sup>\u0394E52<\/sup> patient, an actual DMD treatment, UTRN upregulation was reduced. Altogether, these results indicate that an mRNA decay-based mechanism called transcriptional adaptation<sup>6-8<\/sup> plays a key role in UTRN upregulation in DMD<sup>PTC<\/sup> patients, and they highlight an unexplored therapeutic application of ASOs, as well as ribozymes, in inducing genetic compensation via\u00a0transcriptional adaptation."],"CopyrightInformation":"\u00a9 2025. The Author(s)."},"AuthorList":{"@attributes":{"CompleteYN":"Y"},"Author":[{"@attributes":{"ValidYN":"Y"},"LastName":"Falcucci","ForeName":"Lara","Initials":"L","AffiliationInfo":[{"Affiliation":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."},{"Affiliation":"German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Dooley","ForeName":"Christopher M","Initials":"CM","AffiliationInfo":[{"Affiliation":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."},{"Affiliation":"German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Adamoski","ForeName":"Douglas","Initials":"D","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0000-0001-5062-2586"}],"AffiliationInfo":[{"Affiliation":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Juan","ForeName":"Thomas","Initials":"T","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0000-0002-9654-3717"}],"AffiliationInfo":[{"Affiliation":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."},{"Affiliation":"German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany."},{"Affiliation":"Excellence Cluster Cardio-Pulmonary Institute, Bad Nauheim, Frankfurt, Giessen, Germany."},{"Affiliation":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Martinez","ForeName":"Justin","Initials":"J","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0009-0001-4454-3168"}],"AffiliationInfo":[{"Affiliation":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Georgieva","ForeName":"Angelina M","Initials":"AM","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0000-0002-3215-427X"}],"AffiliationInfo":[{"Affiliation":"Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Mamchaoui","ForeName":"Kamel","Initials":"K","AffiliationInfo":[{"Affiliation":"Sorbonne Universit\u00e9, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Cirzi","ForeName":"Cansu","Initials":"C","AffiliationInfo":[{"Affiliation":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."},{"Affiliation":"Excellence Cluster Cardio-Pulmonary Institute, Bad Nauheim, Frankfurt, Giessen, Germany."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Stainier","ForeName":"Didier Y R","Initials":"DYR","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0000-0002-0382-0026"}],"AffiliationInfo":[{"Affiliation":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. didier.stainier@mpi-bn.mpg.de."},{"Affiliation":"German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany. didier.stainier@mpi-bn.mpg.de."},{"Affiliation":"Excellence Cluster Cardio-Pulmonary Institute, Bad Nauheim, Frankfurt, Giessen, Germany. didier.stainier@mpi-bn.mpg.de."}]}]},"Language":["eng"],"GrantList":{"@attributes":{"CompleteYN":"Y"},"Grant":[{"Agency":"Max Planck Society","Country":""},{"Agency":"European Research Council under the European Union\u2019s research and innovation programmes","Country":""}]},"PublicationTypeList":{"PublicationType":[{"@attributes":{"UI":"D016428"},"@text":"Journal Article"},{"@attributes":{"UI":"D013485"},"@text":"Research Support, Non-U.S. Gov't"}]},"ArticleDate":[{"@attributes":{"DateType":"Electronic"},"Year":"2025","Month":"02","Day":"12"}]},"MedlineJournalInfo":{"Country":"England","MedlineTA":"Nature","NlmUniqueID":"0410462","ISSNLinking":"0028-0836"},"ChemicalList":{"Chemical":[{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D049411"},"@text":"Utrophin"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D016189"},"@text":"Dystrophin"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D018389"},"@text":"Codon, Nonsense"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D016376"},"@text":"Oligonucleotides, Antisense"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D012333"},"@text":"RNA, Messenger"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"C484258"},"@text":"DMD protein, human"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"C483599"},"@text":"UTRN protein, human"}}]},"CitationSubset":["IM"],"MeshHeadingList":{"MeshHeading":[{"DescriptorName":{"@attributes":{"UI":"D020388","MajorTopicYN":"Y"},"@text":"Muscular Dystrophy, Duchenne"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"},{"@attributes":{"UI":"Q000628","MajorTopicYN":"N"},"@text":"therapy"},{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"}]},{"DescriptorName":{"@attributes":{"UI":"D006801","MajorTopicYN":"N"},"@text":"Humans"}},{"DescriptorName":{"@attributes":{"UI":"D049411","MajorTopicYN":"Y"},"@text":"Utrophin"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"},{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"}]},{"DescriptorName":{"@attributes":{"UI":"D015854","MajorTopicYN":"Y"},"@text":"Up-Regulation"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D016189","MajorTopicYN":"N"},"@text":"Dystrophin"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"},{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"}]},{"DescriptorName":{"@attributes":{"UI":"D005091","MajorTopicYN":"N"},"@text":"Exons"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D059365","MajorTopicYN":"N"},"@text":"Nonsense Mediated mRNA Decay"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D018389","MajorTopicYN":"N"},"@text":"Codon, Nonsense"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D020871","MajorTopicYN":"N"},"@text":"RNA Stability"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D016376","MajorTopicYN":"N"},"@text":"Oligonucleotides, Antisense"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D014158","MajorTopicYN":"Y"},"@text":"Transcription, Genetic"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D012333","MajorTopicYN":"N"},"@text":"RNA, Messenger"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D017398","MajorTopicYN":"N"},"@text":"Alternative Splicing"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D000818","MajorTopicYN":"N"},"@text":"Animals"}},{"DescriptorName":{"@attributes":{"UI":"D018485","MajorTopicYN":"N"},"@text":"Muscle Fibers, Skeletal"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"}]},{"DescriptorName":{"@attributes":{"UI":"D016364","MajorTopicYN":"N"},"@text":"Reading Frames"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D051379","MajorTopicYN":"N"},"@text":"Mice"}},{"DescriptorName":{"@attributes":{"UI":"D009154","MajorTopicYN":"N"},"@text":"Mutation"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]}]},"CoiStatement":"Competing interests: The Max Planck Society filed a patent application for ASOs to trigger TA (listing L.F., C.M.D. and D.Y.R.S. as inventors) and another patent application for minigenes containing self-cleaving ribozymes to trigger TA (listing L.F., T.J. and D.Y.R.S. as inventors). The other authors declare no competing interests."},"PubmedData":{"History":{"PubMedPubDate":[{"@attributes":{"PubStatus":"received"},"Year":"2024","Month":"4","Day":"29"},{"@attributes":{"PubStatus":"accepted"},"Year":"2024","Month":"12","Day":"17"},{"@attributes":{"PubStatus":"medline"},"Year":"2025","Month":"3","Day":"13","Hour":"6","Minute":"28"},{"@attributes":{"PubStatus":"pubmed"},"Year":"2025","Month":"2","Day":"13","Hour":"0","Minute":"22"},{"@attributes":{"PubStatus":"entrez"},"Year":"2025","Month":"2","Day":"12","Hour":"23","Minute":"34"},{"@attributes":{"PubStatus":"pmc-release"},"Year":"2025","Month":"2","Day":"12"}]},"PublicationStatus":"ppublish","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"39939773"},{"@attributes":{"IdType":"pmc"},"@text":"PMC11903304"},{"@attributes":{"IdType":"doi"},"@text":"10.1038\/s41586-024-08539-x"},{"@attributes":{"IdType":"pii"},"@text":"10.1038\/s41586-024-08539-x"}]},"ReferenceList":[{"Reference":[{"Citation":"Blake, D. 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