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

ABSTRACT: 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 MBN

SUBMITTER: Musiala-Kierklo N 

PROVIDER: S-EPMC12364543 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature