Preloader

Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats

  • Lukong, K. E., Chang, K., Khandjian, E. W. & Richard, S. RNA-binding proteins in human genetic disease. Trends Genet. 24, 416–425 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • Lin, X. et al. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum. Mol. Genet. 15, 2087–2097 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • Kanadia, R. N. et al. A muscleblind knockout model for myotonic dystrophy. Science 302, 1978–1980 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • Brook, J. D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3’ end of a transcript encoding a protein kinase family member. Cell 69, 385 (1992).

    CAS 
    PubMed 

    Google Scholar 

  • Taneja, K. L., McCurrach, M., Schalling, M., Housman, D. & Singer, R. H. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J. Cell Biol. 128, 995–1002 (1995).

    CAS 
    PubMed 

    Google Scholar 

  • Miller, J. W. et al. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 19, 4439–4448 (2000).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee, K.-Y. et al. Compound loss of muscleblind-like function in myotonic dystrophy. EMBO Mol. Med. 5, 1887–1900 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nakamori, M. et al. Splicing biomarkers of disease severity in myotonic dystrophy. Ann. Neurol. 74, 862–872 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mankodi, A. et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol. Cell 10, 35–44 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • Savkur, R. S., Philips, A. V. & Cooper, T. A. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat. Genet. 29, 40–47 (2001).

    CAS 
    PubMed 

    Google Scholar 

  • Fugier, C. et al. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat. Med. 17, 720–725 (2011).

    CAS 
    PubMed 

    Google Scholar 

  • Rau, F. et al. Abnormal splicing switch of DMD’s penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nat. Commun. 6, 7205 (2015).

    PubMed 

    Google Scholar 

  • Freyermuth, F. et al. Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat. Commun. 7, 11067 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wheeler, T. M. et al. Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325, 336–339 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wheeler, T. M. et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488, 111–115 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Klein, A. F. et al. Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice. J. Clin. Invest. 129, 4739–4744 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Warf, M. B., Nakamori, M., Matthys, C. M., Thornton, C. A. & Berglund, J. A. Pentamidine reverses the splicing defects associated with myotonic dystrophy. Proc. Natl Acad. Sci. USA 106, 18551–18556 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • García-López, A., Llamusí, B., Orzáez, M., Pérez-Payá, E. & Artero, R. D. In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models. Proc. Natl Acad. Sci. USA 108, 11866–11871 (2011).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Angelbello, A. J. et al. Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model. Proc. Natl Acad. Sci. USA 116, 7799–7804 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nakamori, M., Taylor, K., Mochizuki, H., Sobczak, K. & Takahashi, M. P. Oral administration of erythromycin decreases RNA toxicity in myotonic dystrophy. Ann. Clin. Transl. Neurol. 3, 42–54 (2016).

    CAS 
    PubMed 

    Google Scholar 

  • Batra, R. et al. Elimination of toxic microsatellite repeat expansion RNA by RNA-targeting Cas9. Cell 170, 899–912.e10 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Batra, R. et al. The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1. Nat. Biomed. Eng. 5, 157–168 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Zhang, N., Bewick, B., Xia, G., Furling, D. & Ashizawa, T. A CRISPR-Cas13a based strategy that tracks and degrades toxic RNA in myotonic dystrophy type 1. Front. Genet. 11, 594576 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kanadia, R. N. et al. Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc. Natl Acad. Sci. USA 103, 11748–11753 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hale, M. A. et al. An engineered RNA binding protein with improved splicing regulation. Nucleic Acids Res. 46, 3152–3168 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Konieczny, P., Stepniak-Konieczna, E. & Sobczak, K. MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res. 42, 10873–10887 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kanadia, R. N. et al. Developmental expression of mouse muscleblind genes Mbnl1, Mbnl2 and Mbnl3. Gene Expr. Patterns 3, 459–462 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • Fardaei, M. et al. Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum. Mol. Genet. 11, 805–814 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • Chen, G. et al. Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy. Neurobiol. Dis. 112, 35–48 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chamberlain, C. M. & Ranum, L. P. W. Mouse model of muscleblind-like 1 overexpression: skeletal muscle effects and therapeutic promise. Hum. Mol. Genet. 21, 4645–4654 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yadava, R. S. et al. MBNL1 overexpression is not sufficient to rescue the phenotypes in a mouse model of RNA toxicity. Hum. Mol. Genet. 28, 2330–2338 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shukla, T. N., Song, J. & Campbell, Z. T. Molecular entrapment by RNA: an emerging tool for disrupting protein-RNA interactions in vivo. RNA Biol. 17, 417–424 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tran, H. et al. Analysis of exonic regions involved in nuclear localization, splicing activity, and dimerization of Muscleblind-like-1 isoforms. J. Biol. Chem. 286, 16435–16446 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Grammatikakis, I., Goo, Y.-H., Echeverria, G. V. & Cooper, T. A. Identification of MBNL1 and MBNL3 domains required for splicing activation and repression. Nucleic Acids Res. 39, 2769–2780 (2011).

    CAS 
    PubMed 

    Google Scholar 

  • Warf, M. B. & Berglund, J. A. MBNL binds similar RNA structures in the CUG repeats of myotonic dystrophy and its pre-mRNA substrate cardiac troponin T. RNA 13, 2238–2251 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wagner, S. D. et al. Dose-dependent regulation of alternative splicing by MBNL proteins reveals biomarkers for myotonic dystrophy. PLoS Genet. 12, e1006316 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Arandel, L. et al. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds. Dis. Model. Mech. 10, 487–497 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jain, A. & Vale, R. D. RNA phase transitions in repeat expansion disorders. Nature 546, 243–247 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zincarelli, C., Soltys, S., Rengo, G. & Rabinowitz, J. E. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol. Ther. 16, 1073–1080 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • Tanner, M. K., Tang, Z. & Thornton, C. A. Targeted splice sequencing reveals RNA toxicity and therapeutic response in myotonic dystrophy. Nucleic Acids Res. 49, 2240–2254 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, E. T. et al. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150, 710–724 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wheeler, T. M., Lueck, J. D., Swanson, M. S., Dirksen, R. T. & Thornton, C. A. Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J. Clin. Invest. 117, 3952–3957 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sznajder, J. et al. Mechanistic determinants of MBNL activity. Nucleic Acids Res. 44, 10326–10342 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • François, V. et al. Selective silencing of mutated mRNAs in DM1 by using modified hU7-snRNAs. Nat. Struct. Mol. Biol. 18, 85–87 (2011).

    PubMed 

    Google Scholar 

  • Liquori, C. L. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293, 864–867 (2001).

    CAS 
    PubMed 

    Google Scholar 

  • Sellier, C. et al. rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences. Nat. Commun. 9, 2009 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Daughters, R. S. et al. RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet. 5, e1000600 (2009).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Rudnicki, D. D. et al. Huntington’s disease—like 2 is associated with CUG repeat-containing RNA foci. Ann. Neurol. 61, 272–282 (2007).

    CAS 
    PubMed 

    Google Scholar 

  • Swinnen, B., Robberecht, W. & van den Bosch, L. RNA toxicity in non-coding repeat expansion disorders. EMBO J. 39, e101112 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Chaouch, S. et al. Immortalized skin fibroblasts expressing conditional MyoD as a renewable and reliable source of converted human muscle cells to assess therapeutic strategies for muscular dystrophies: validation of an exon-skipping approach to restore dystrophin in Duchenne muscular dystrophy cells. Hum. Gene Ther. 20, 784–790 (2009).

    CAS 
    PubMed 

    Google Scholar 

  • Snyder, R. O. et al. Efficient and stable adeno-associated virus-mediated transduction in the skeletal muscle of adult immunocompetent mice. Hum. Gene Ther. 8, 1891–1900 (1997).

    CAS 
    PubMed 

    Google Scholar 

  • Moulay, G. et al. Alternative splicing of clathrin heavy chain contributes to the switch from coated pits to plaques. J. Cell Biol. 219, e201912061 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cooper, T. A. Muscle-specific splicing of a heterologous exon mediated by a single muscle-specific splicing enhancer from the cardiac troponin T gene. Mol. Cell. Biol. 18, 4519–4525 (1998).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Laurent, F.-X. et al. New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats. Nucleic Acids Res. 40, 3159–3171 (2012).

    CAS 
    PubMed 

    Google Scholar 

  • Klein, A. F., Arandel, L., Marie, J. & Furling, D. FISH protocol for myotonic dystrophy type 1 cells. Methods Mol. Biol. 2056, 203–215 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Byron, M., Hall, L. L. & Lawrence, J. B. A multifaceted FISH approach to study endogenous RNAs and DNAs in native nuclear and cell structures. Curr. Protoc. Hum. Genet. Chapter 4, Unit 4.15 (2013).

    PubMed 

    Google Scholar 

  • Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).

    CAS 

    Google Scholar 

  • Bolte, S. & Cordelières, F. P. A guided tour into subcellular colocalization analysis in light microscopy. J. Microsc. 224, 213–232 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet. J. 17, 10–12 (2011).

    Google Scholar 

  • Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    CAS 

    Google Scholar 

  • Di Tommaso, P. et al. Nextflow enables reproducible computational workflows. Nat. Biotechnol. 11, 316–319 (2017).

    Google Scholar 

  • Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Shen, S. et al. rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-seq data. Proc. Natl Acad. Sci. USA 111, E5593–E5601 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, J., Bardes, E. E., Aronow, B. J. & Jegga, A. G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 37, W305–W311 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hourdé, C. et al. Sustained peripheral arterial insufficiency durably impairs normal and regenerating skeletal muscle function. J. Physiol. Sci. 56, 361–367 (2006).

    PubMed 

    Google Scholar 

  • Source link