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Promoter-targeted small RNA duplexes increase MBNL1 transcription and mitigate myotonic dystrophy-associated spliceopathy

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cris.virtual.author-orcid0000-0002-7387-1013
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cris.virtualsource.author-orcid188d1b2b-1b4d-4337-8675-9f8a1a261c6f
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dc.abstract.enFunctional depletion of Muscleblind-like (MBNL) proteins is a key trigger of myotonic dystrophy (DM)-associated alternative splicing (AltS) defects. To overcome MBNL insufficiency in DM cell models, we harnessed a conserved endogenous mechanism of RNA activation (RNAa) via rationally designed small activating RNA (saRNA) targeted to the most active promoter of MBNL1 gene. We report on two lead saRNA duplexes that stimulated MBNL1 transcription via an on-site mechanism that involves AGO2-mediated loading of the antisense strand onto target sequence, followed by recruitment of RNAPII and auxiliary RNAa pathway components. We demonstrate that neither the antisense lncRNA MBNL1-AS1 overlapping MBNL1 promoter nor promoter-associated cryptic RNAs are mechanistically involved in saRNA-induced MBNL1 gene activation. Our data highlight putative transcription factors whose binding recruitment via identified saRNAs may affect MBNL1 expression. Most importantly, we show that RNAa-based approach upregulates MBNL1 protein content in distinct DM cell models and corrects the AltS of multiple MBNL1-regulated biomarker exons, underscoring the feasibility of adapting saRNA into novel therapeutic designs. This is the first report that site-specific augmentation of the endogenous MBNL1 transcription mitigates disease-associated AltS defects and as such, it offers new perspectives into therapeutic options against DM.
dc.affiliationWydział Rolnictwa, Ogrodnictwa i Biotechnologii
dc.affiliation.instituteKatedra Biochemii i Biotechnologii
dc.contributor.authorMusiała-Kierklo, Nikola
dc.contributor.authorPlewka, Patrycja
dc.contributor.authorJasiok, Adam
dc.contributor.authorStępniak-Konieczna, Ewa
dc.date.access2025-08-21
dc.date.accessioned2025-08-21T07:08:52Z
dc.date.available2025-08-21T07:08:52Z
dc.date.copyright2025-08-20
dc.date.issued2025
dc.description.abstract<jats:title>Abstract</jats:title> <jats:p>Functional depletion of Muscleblind-like (MBNL) proteins is a key trigger of myotonic dystrophy (DM)-associated alternative splicing (AltS) defects. To overcome MBNL insufficiency in DM cell models, we harnessed a conserved endogenous mechanism of RNA activation (RNAa) via rationally designed small activating RNA (saRNA) targeted to the most active promoter of MBNL1 gene. We report on two lead saRNA duplexes that stimulated MBNL1 transcription via an on-site mechanism that involves AGO2-mediated loading of the antisense strand onto target sequence, followed by recruitment of RNAPII and auxiliary RNAa pathway components. We demonstrate that neither the antisense lncRNA MBNL1-AS1 overlapping MBNL1 promoter nor promoter-associated cryptic RNAs are mechanistically involved in saRNA-induced MBNL1 gene activation. Our data highlight putative transcription factors whose binding recruitment via identified saRNAs may affect MBNL1 expression. Most importantly, we show that RNAa-based approach upregulates MBNL1 protein content in distinct DM cell models and corrects the AltS of multiple MBNL1-regulated biomarker exons, underscoring the feasibility of adapting saRNA into novel therapeutic designs. This is the first report that site-specific augmentation of the endogenous MBNL1 transcription mitigates disease-associated AltS defects and as such, it offers new perspectives into therapeutic options against DM.</jats:p>
dc.description.accesstimeat_publication
dc.description.bibliographyil., bibliogr.
dc.description.financepublication_nocost
dc.description.financecost0,00
dc.description.if13,1
dc.description.number15 (28 August 2025)
dc.description.points200
dc.description.versionfinal_published
dc.description.volume53
dc.identifier.doi10.1093/nar/gkaf756
dc.identifier.eissn1362-4962
dc.identifier.issn0305-1048
dc.identifier.urihttps://sciencerep.up.poznan.pl/handle/item/4322
dc.identifier.weblinkhttps://academic.oup.com/nar/article/53/15/gkaf756/8237897
dc.languageen
dc.relation.ispartofNucleic Acids Research
dc.relation.pagesgkaf756
dc.rightsCC-BY
dc.sciencecloudsend
dc.share.typeOPEN_JOURNAL
dc.titlePromoter-targeted small RNA duplexes increase MBNL1 transcription and mitigate myotonic dystrophy-associated spliceopathy
dc.typeJournalArticle
dspace.entity.typePublication
oaire.citation.issue15
oaire.citation.volume53