Articoli di riviste: "MuscleBlind Like (MBNL)"

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Bargiela, Ariadna, Maria Sabater-Arcis, Jorge Espinosa-Espinosa, Miren Zulaica, Adolfo Lopez de Munain e Ruben Artero. "Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models". Proceedings of the National Academy of Sciences 116, n. 50 (21 novembre 2019): 25203–13. http://dx.doi.org/10.1073/pnas.1820297116.

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Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3′ UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in Drosophila and mouse (HSALR) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSALR mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.

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Voss, Dillon, Anthony Sloan, Eli Bar e Eli Bar. "TAMI-49. THE ALTERNATIVE SPLICING FACTOR MBNL1 INHIBITS GLIOBLASTOMA TUMOR INITIATION AND PROGRESSION BY REDUCING HYPOXIA-INDUCED STEMNESS". Neuro-Oncology 22, Supplement_2 (novembre 2020): ii223—ii224. http://dx.doi.org/10.1093/neuonc/noaa215.936.

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Abstract Muscleblind-like-proteins (MBNL) belong to a family of tissue-specific RNA metabolism-regulators that control pre-messenger RNA-splicing (AS). Inactivation of MBNL causes an adult-to-fetal AS transition, resulting in the development of myotonic dystrophy. We have previously shown that the aggressive brain cancer, glioblastoma (GBM), maintains stem-like features (GSC) through hypoxia-induced responses. Accordingly, we hypothesized that the hypoxia-induced responses in GBM might also include MBNL-based AS to promote tumor progression. When cultured in hypoxia, GSCs rapidly export MBNL1 out of the nucleus resulting in significant inhibition of MBNL1 activity. Notably, the hypoxia-regulated inhibition of MBNL1 also resulted in evidence of adult-to-fetal alternative splicing transitions. Forced expression of a constitutively active isoform of MBNL1 inhibited GSC self-renewal and tumor initiation in orthotopic transplantation models. Using a tetracycline-inducible system, induced expression of MBNL1 in established orthotopic tumors dramatically inhibited tumor progression resulting in a significant prolongation of survival. This study reveals that MBNL1 plays an essential role in GBM stemness and tumor progression, whereby hypoxic responses within the tumor inhibit MBNL1 activity, promoting stem-like phenotypes and tumor growth. Reversing these effects on MBNL1 may, therefore, yield potent tumor-suppressor activities, uncovering new therapeutic opportunities to counter this devastating disease.

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Overby, Sarah, Estefanía Cerro-Herreros, Jorge Espinosa-Espinosa, Irene González-Martínez, Nerea Moreno, Juan Fernández-Costa, Jordina Balaguer-Trias et al. "BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSALR Mice". Pharmaceutics 15, n. 4 (31 marzo 2023): 1118. http://dx.doi.org/10.3390/pharmaceutics15041118.

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The symptoms of Myotonic Dystrophy Type 1 (DM1) are multi-systemic and life-threatening. The neuromuscular disorder is rooted in a non-coding CTG microsatellite expansion in the DM1 protein kinase (DMPK) gene that, upon transcription, physically sequesters the Muscleblind-like (MBNL) family of splicing regulator proteins. The high-affinity binding occurring between the proteins and the repetitions disallow MBNL proteins from performing their post-transcriptional splicing regulation leading to downstream molecular effects directly related to disease symptoms such as myotonia and muscle weakness. In this study, we build on previously demonstrated evidence showing that the silencing of miRNA-23b and miRNA-218 can increase MBNL1 protein in DM1 cells and mice. Here, we use blockmiR antisense technology in DM1 muscle cells, 3D mouse-derived muscle tissue, and in vivo mice to block the binding sites of these microRNAs in order to increase MBNL translation into protein without binding to microRNAs. The blockmiRs show therapeutic effects with the rescue of mis-splicing, MBNL subcellular localization, and highly specific transcriptomic expression. The blockmiRs are well tolerated in 3D mouse skeletal tissue inducing no immune response. In vivo, a candidate blockmiR also increases Mbnl1/2 protein and rescues grip strength, splicing, and histological phenotypes.

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Yadava, Ramesh S., Mahua Mandal e Mani S. Mahadevan. "Studying the Effect of MBNL1 and MBNL2 Loss in Skeletal Muscle Regeneration". International Journal of Molecular Sciences 25, n. 5 (26 febbraio 2024): 2687. http://dx.doi.org/10.3390/ijms25052687.

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Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy. We used a BaCl2-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in Mbnl1∆E3/∆E3 and Mbnl2∆E2/∆E2 knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in Mbnl1 and Mbnl2 knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in Mbnl1∆E3/∆E3/ Mbnl2∆E2/+ mice showed increased histopathology but no deleterious reductions in MuSC numbers and only a slight increase in collagen deposition. These results suggest that factors beyond the loss of MBNL1/MBNL2 and the associated spliceopathy are likely to play a key role in the defects in skeletal muscle regeneration and deleterious effects on MuSCs that are seen in mouse models of RNA toxicity due to expanded CUG repeats.

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González, Àlex L., Daniel Fernández-Remacha, José Ignacio Borrell, Jordi Teixidó e Roger Estrada-Tejedor. "Cognate RNA-Binding Modes by the Alternative-Splicing Regulator MBNL1 Inferred from Molecular Dynamics". International Journal of Molecular Sciences 23, n. 24 (18 dicembre 2022): 16147. http://dx.doi.org/10.3390/ijms232416147.

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The muscleblind-like protein family (MBNL) plays a prominent role in the regulation of alternative splicing. Consequently, the loss of MBNL function resulting from sequestration by RNA hairpins triggers the development of a neuromuscular disease called myotonic dystrophy (DM). Despite the sequence and structural similarities between the four zinc-finger domains that form MBNL1, recent studies have revealed that the four binding domains have differentiated splicing activity. The dynamic behaviors of MBNL1 ZnFs were simulated using conventional molecular dynamics (cMD) and steered molecular dynamics (sMD) simulations of a structural model of MBNL1 protein to provide insights into the binding selectivity of the four zinc-finger (ZnF) domains toward the GpC steps in YGCY RNA sequence. In accordance with previous studies, our results suggest that both global and local residue fluctuations on each domain have great impacts on triggering alternative splicing, indicating that local motions in RNA-binding domains could modulate their affinity and specificity. In addition, all four ZnF domains provide a distinct RNA-binding environment in terms of structural sampling and mobility that may be involved in the differentiated MBNL1 splicing events reported in the literature.

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Verbeeren, Jens, Joana Teixeira e Susana M. D. A. Garcia. "The Muscleblind-like protein MBL-1 regulates microRNA expression in Caenorhabditis elegans through an evolutionarily conserved autoregulatory mechanism". PLOS Genetics 19, n. 12 (22 dicembre 2023): e1011109. http://dx.doi.org/10.1371/journal.pgen.1011109.

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The Muscleblind-like (MBNL) family is a highly conserved set of RNA-binding proteins (RBPs) that regulate RNA metabolism during the differentiation of various animal tissues. Functional insufficiency of MBNL affects muscle and central nervous system development, and contributes to the myotonic dystrophies (DM), a set of incurable multisystemic disorders. Studies on the regulation of MBNL genes are essential to provide insight into the gene regulatory networks controlled by MBNL proteins and to understand how dysregulation within these networks causes disease. In this study, we demonstrate the evolutionary conservation of an autoregulatory mechanism that governs the function of MBNL proteins by generating two distinct protein isoform types through alternative splicing. Our aim was to further our understanding of the regulatory principles that underlie this conserved feedback loop in a whole-organismal context, and to address the biological significance of the respective isoforms. Using an alternative splicing reporter, our studies show that, during development of the Caenorhabditis elegans central nervous system, the orthologous mbl-1 gene shifts production from long protein isoforms that localize to the nucleus to short isoforms that also localize to the cytoplasm. Using isoform-specific CRISPR/Cas9-generated strains, we showed that expression of short MBL-1 protein isoforms is required for healthy neuromuscular function and neurodevelopment, while expression of long MBL-1 protein isoforms is dispensable, emphasizing a key role for cytoplasmic functionalities of the MBL-1 protein. Furthermore, RNA-seq and lifespan analyses indicated that short MBL-1 isoforms are crucial regulators of miRNA expression and, in consequence, required for normal lifespan. In conclusion, this study provides support for the disruption of cytoplasmic RNA metabolism as a contributor in myotonic dystrophy and paves the way for further exploration of miRNA regulation through MBNL proteins during development and in disease models.

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Terenzi, Fulvia, e Andrea N. Ladd. "Conserved developmental alternative splicing of muscleblind-like (MBNL) transcripts regulates MBNL localization and activity". RNA Biology 7, n. 1 (gennaio 2010): 43–55. http://dx.doi.org/10.4161/rna.7.1.10401.

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López-Martínez, Andrea, Patricia Soblechero-Martín, Laura de-la-Puente-Ovejero, Gisela Nogales-Gadea e Virginia Arechavala-Gomeza. "An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I". Genes 11, n. 9 (22 settembre 2020): 1109. http://dx.doi.org/10.3390/genes11091109.

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Abstract (sommario):

Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3′ untranslated region (3′UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result in protein trapping by expanded transcripts, a decreased DMPK translation and the disruption of the chromatin structure, affecting neighboring genes expression. The muscleblind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) are two families of tissue-specific regulators of developmentally programmed alternative splicing that act as antagonist regulators of several pre-mRNA targets, including troponin 2 (TNNT2), insulin receptor (INSR), chloride channel 1 (CLCN1) and MBNL2. Sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology, inducing a spliceopathy that leads to a developmental remodelling of the transcriptome due to an adult-to-foetal splicing switch, which results in the loss of cell function and viability. Moreover, recent studies indicate that additional pathogenic mechanisms may also contribute to disease pathology, including a misregulation of cellular mRNA translation, localization and stability. This review focuses on the cause and effects of MBNL and CELF1 deregulation in DM1, describing the molecular mechanisms underlying alternative splicing misregulation for a deeper understanding of DM1 complexity. To contribute to this analysis, we have prepared a comprehensive list of transcript alterations involved in DM1 pathogenesis, as well as other deregulated mRNA processing pathways implications.

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Sznajder, Łukasz J., e Maurice S. Swanson. "Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy". International Journal of Molecular Sciences 20, n. 13 (9 luglio 2019): 3365. http://dx.doi.org/10.3390/ijms20133365.

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Short tandem repeat (STR) or microsatellite, expansions underlie more than 50 hereditary neurological, neuromuscular and other diseases, including myotonic dystrophy types 1 (DM1) and 2 (DM2). Current disease models for DM1 and DM2 propose a common pathomechanism, whereby the transcription of mutant DMPK (DM1) and CNBP (DM2) genes results in the synthesis of CUG and CCUG repeat expansion (CUGexp, CCUGexp) RNAs, respectively. These CUGexp and CCUGexp RNAs are toxic since they promote the assembly of ribonucleoprotein (RNP) complexes or RNA foci, leading to sequestration of Muscleblind-like (MBNL) proteins in the nucleus and global dysregulation of the processing, localization and stability of MBNL target RNAs. STR expansion RNAs also form phase-separated gel-like droplets both in vitro and in transiently transfected cells, implicating RNA-RNA multivalent interactions as drivers of RNA foci formation. Importantly, the nucleation and growth of these nuclear foci and transcript misprocessing are reversible processes and thus amenable to therapeutic intervention. In this review, we provide an overview of potential DM1 and DM2 pathomechanisms, followed by a discussion of MBNL functions in RNA processing and how multivalent interactions between expanded STR RNAs and RNA-binding proteins (RBPs) promote RNA foci assembly.

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Tanner, Matthew K., Zhenzhi Tang e Charles A. Thornton. "Targeted splice sequencing reveals RNA toxicity and therapeutic response in myotonic dystrophy". Nucleic Acids Research 49, n. 4 (27 gennaio 2021): 2240–54. http://dx.doi.org/10.1093/nar/gkab022.

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Abstract Biomarker-driven trials hold promise for therapeutic development in chronic diseases, such as muscular dystrophy. Myotonic dystrophy type 1 (DM1) involves RNA toxicity, where transcripts containing expanded CUG-repeats (CUGexp) accumulate in nuclear foci and sequester splicing factors in the Muscleblind-like (Mbnl) family. Oligonucleotide therapies to mitigate RNA toxicity have emerged but reliable measures of target engagement are needed. Here we examined muscle transcriptomes in mouse models of DM1 and found that CUGexp expression or Mbnl gene deletion cause similar dysregulation of alternative splicing. We selected 35 dysregulated exons for further study by targeted RNA sequencing. Across a spectrum of mouse models, the individual splice events and a composite index derived from all events showed a graded response to decrements of Mbnl or increments of CUGexp. Antisense oligonucleotides caused prompt reduction of CUGexp RNA and parallel correction of the splicing index, followed by subsequent elimination of myotonia. These results suggest that targeted splice sequencing may provide a sensitive and reliable way to assess therapeutic impact in DM1.

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López Castel, Arturo, Sarah Joann Overby e Rubén Artero. "MicroRNA-Based Therapeutic Perspectives in Myotonic Dystrophy". International Journal of Molecular Sciences 20, n. 22 (9 novembre 2019): 5600. http://dx.doi.org/10.3390/ijms20225600.

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Myotonic dystrophy involves two types of chronically debilitating rare neuromuscular diseases: type 1 (DM1) and type 2 (DM2). Both share similarities in molecular cause, clinical signs, and symptoms with DM2 patients usually displaying milder phenotypes. It is well documented that key clinical symptoms in DM are associated with a strong mis-regulation of RNA metabolism observed in patient’s cells. This mis-regulation is triggered by two leading DM-linked events: the sequestration of Muscleblind-like proteins (MBNL) and the mis-regulation of the CUGBP RNA-Binding Protein Elav-Like Family Member 1 (CELF1) that cause significant alterations to their important functions in RNA processing. It has been suggested that DM1 may be treatable through endogenous modulation of the expression of MBNL and CELF1 proteins. In this study, we analyzed the recent identification of the involvement of microRNA (miRNA) molecules in DM and focus on the modulation of these miRNAs to therapeutically restore normal MBNL or CELF1 function. We also discuss additional prospective miRNA targets, the use of miRNAs as disease biomarkers, and additional promising miRNA-based and miRNA-targeting drug development strategies. This review provides a unifying overview of the dispersed data on miRNA available in the context of DM.

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Holm, Frida, Eva Hellqvist, Cayla N. Mason, Shawn A. Ali, Nathaniel Delos-Santos, Christian L. Barrett, Hye-Jung Chun et al. "Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal". Proceedings of the National Academy of Sciences 112, n. 50 (30 novembre 2015): 15444–49. http://dx.doi.org/10.1073/pnas.1506943112.

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Formative research suggests that a human embryonic stem cell-specific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8–10, and BC LSC proliferation. Although isoform-specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region - ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche-dependent manner. In summary, MBNL3 down-regulation–related reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination.

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Huang, Hu, Karl J. Wahlin, Minda McNally, Natasha D. Irving e Ruben Adler. "Developmental regulation of muscleblind-like (MBNL) gene expression in the chicken embryo retina". Developmental Dynamics 237, n. 1 (gennaio 2008): 286–96. http://dx.doi.org/10.1002/dvdy.21408.

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Tabaglio, Tommaso, Diana HP Low, Winnie Koon Lay Teo, Pierre Alexis Goy, Piotr Cywoniuk, Heike Wollmann, Jessica Ho et al. "MBNL1 alternative splicing isoforms play opposing roles in cancer". Life Science Alliance 1, n. 5 (7 settembre 2018): e201800157. http://dx.doi.org/10.26508/lsa.201800157.

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The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

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Penna, Matthew S., Rong-Chi Hu, George G. Rodney e Thomas A. Cooper. "The role ofLimch1alternative splicing in skeletal muscle function". Life Science Alliance 6, n. 6 (28 marzo 2023): e202201868. http://dx.doi.org/10.26508/lsa.202201868.

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Postnatal skeletal muscle development is a highly dynamic period associated with widespread alternative splicing changes required to adapt tissues to adult function. These splicing events have significant implications because the reversion of adult mRNA isoforms to fetal isoforms is observed in forms of muscular dystrophy. LIMCH1 is a stress fiber–associated protein that is alternatively spliced to generate uLIMCH1, a ubiquitously expressed isoform, and mLIMCH1, a skeletal muscle–specific isoform containing six additional exons simultaneously included after birth in the mouse. CRISPR/Cas9 was used to delete the six alternatively spliced exons of LIMCH1 in mice, thereby forcing the constitutive expression of the predominantly fetal isoform, uLIMCH1. mLIMCH1 knockout mice had significant grip strength weakness in vivo, and maximum force generated was decreased ex vivo. Calcium-handling deficits were observed during myofiber stimulation that could explain the mechanism by which mLIMCH1 knockout leads to muscle weakness. In addition,LIMCH1is mis-spliced in myotonic dystrophy type 1, with the muscleblind-like (MBNL) family of proteins acting as the likely major regulator ofLimch1alternative splicing in skeletal muscle.

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Xie, Jianxin, Wei Zou, Madina Tugizova, Kang Shen e Xiangming Wang. "MBL-1 and EEL-1 affect the splicing and protein levels of MEC-3 to control dendrite complexity". PLOS Genetics 19, n. 9 (20 settembre 2023): e1010941. http://dx.doi.org/10.1371/journal.pgen.1010941.

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Transcription factors (TFs) play critical roles in specifying many aspects of neuronal cell fate including dendritic morphology. How TFs are accurately regulated during neuronal morphogenesis is not fully understood. Here, we show that LIM homeodomain protein MEC-3, the key TF for C. elegans PVD dendrite morphogenesis, is regulated by both alternative splicing and an E3 ubiquitin ligase. The mec-3 gene generates several transcripts by alternative splicing. We find that mbl-1, the orthologue of the muscular dystrophy disease gene muscleblind-like (MBNL), is required for PVD dendrite arbor formation. Our data suggest mbl-1 regulates the alternative splicing of mec-3 to produce its long isoform. Deleting the long isoform of mec-3(deExon2) causes reduction of dendrite complexity. Through a genetic modifier screen, we find that mutation in the E3 ubiquitin ligase EEL-1 suppresses mbl-1 phenotype. eel-1 mutants also suppress mec-3(deExon2) mutant but not the mec-3 null phenotype. Loss of EEL-1 alone leads to excessive dendrite branches. Together, these results indicate that MEC-3 is fine-tuned by alternative splicing and the ubiquitin system to produce the optimal level of dendrite branches.

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Li, Moyi, Yan Zhuang, Ranjan Batra, James D. Thomas, Mao Li, Curtis A. Nutter, Marina M. Scotti et al. "HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy". Proceedings of the National Academy of Sciences 117, n. 10 (21 febbraio 2020): 5472–77. http://dx.doi.org/10.1073/pnas.1907297117.

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Studies on myotonic dystrophy type 1 (DM1) have led to the RNA-mediated disease model for hereditary disorders caused by noncoding microsatellite expansions. This model proposes that DM1 disease manifestations are caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions (CUGexp) leading to decreased muscleblind-like, but increased CUGBP1/ETR3-like factor 1 (CELF1), alternative splicing activities. Here, we test this model in vivo, using the mouse HSALR poly(CUG) model for DM1 and recombinant adeno-associated virus (rAAV)-mediated transduction of specific splicing factors. Surprisingly, systemic overexpression of HNRNPA1, not previously linked to DM1, also shifted DM1-relevant splicing targets to fetal isoforms, resulting in more severe muscle weakness/myopathy as early as 4 to 6 wk posttransduction, whereas rAAV controls were unaffected. Overexpression of HNRNPA1 promotes fetal exon inclusion of representative DM1-relevant splicing targets in differentiated myoblasts, and HITS-CLIP of rAAV-mycHnrnpa1-injected muscle revealed direct interactions of HNRNPA1 with these targets in vivo. Similar to CELF1, HNRNPA1 protein levels decrease during postnatal development, but are elevated in both regenerating mouse muscle and DM1 skeletal muscle. Our studies suggest that CUGexp RNA triggers abnormal expression of multiple nuclear RNA binding proteins, including CELF1 and HNRNPA1, that antagonize MBNL activity to promote fetal splicing patterns.

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Stepniak-Konieczna, Ewa, Patryk Konieczny, Piotr Cywoniuk, Julia Dluzewska e Krzysztof Sobczak. "AON-induced splice-switching and DMPK pre-mRNA degradation as potential therapeutic approaches for Myotonic Dystrophy type 1". Nucleic Acids Research 48, n. 5 (22 gennaio 2020): 2531–43. http://dx.doi.org/10.1093/nar/gkaa007.

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Abstract Expansion of an unstable CTG repeat in the 3′UTR of the DMPK gene causes Myotonic Dystrophy type 1 (DM1). CUG-expanded DMPK transcripts (CUGexp) sequester Muscleblind-like (MBNL) alternative splicing regulators in ribonuclear inclusions (foci), leading to abnormalities in RNA processing and splicing. To alleviate the burden of CUGexp, we tested therapeutic approach utilizing antisense oligonucleotides (AONs)-mediated DMPK splice-switching and degradation of mutated pre-mRNA. Experimental design involved: (i) skipping of selected constitutive exons to induce frameshifting and decay of toxic mRNAs by an RNA surveillance mechanism, and (ii) exclusion of the alternative exon 15 (e15) carrying CUGexp from DMPK mRNA. While first strategy failed to stimulate DMPK mRNA decay, exclusion of e15 enhanced DMPK nuclear export but triggered accumulation of potentially harmful spliced out pre-mRNA fragment containing CUGexp. Neutralization of this fragment with antisense gapmers complementary to intronic sequences preceding e15 failed to diminish DM1-specific spliceopathy due to AONs’ chemistry-related toxicity. However, intronic gapmers alone reduced the level of DMPK mRNA and mitigated DM1-related cellular phenotypes including spliceopathy and nuclear foci. Thus, a combination of the correct chemistry and experimental approach should be carefully considered to design a safe AON-based therapeutic strategy for DM1.

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Wang, Eric T., Daniel Treacy, Katy Eichinger, Adam Struck, Joseph Estabrook, Hailey Olafson, Thomas T. Wang et al. "Transcriptome alterations in myotonic dystrophy skeletal muscle and heart". Human Molecular Genetics 28, n. 8 (17 dicembre 2018): 1312–21. http://dx.doi.org/10.1093/hmg/ddy432.

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Abstract Myotonic dystrophy (dystrophia myotonica, DM) is a multi-systemic disease caused by expanded CTG or CCTG microsatellite repeats. Characterized by symptoms in muscle, heart and central nervous system, among others, it is one of the most variable diseases known. A major pathogenic event in DM is the sequestration of muscleblind-like proteins by CUG or CCUG repeat-containing RNAs transcribed from expanded repeats, and differences in the extent of MBNL sequestration dependent on repeat length and expression level may account for some portion of the variability. However, many other cellular pathways are reported to be perturbed in DM, and the severity of specific disease symptoms varies among individuals. To help understand this variability and facilitate research into DM, we generated 120 RNASeq transcriptomes from skeletal and heart muscle derived from healthy and DM1 biopsies and autopsies. A limited number of DM2 and Duchenne muscular dystrophy samples were also sequenced. We analyzed splicing and gene expression, identified tissue-specific changes in RNA processing and uncovered transcriptome changes strongly correlating with muscle strength. We created a web resource at http://DMseq.org that hosts raw and processed transcriptome data and provides a lightweight, responsive interface that enables browsing of processed data across the genome.

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Holm, Frida Linnea, Eva Hellqvist, Cayla N. Mason, Shawn Ali, Nathaniel Delos Santos, Christian Barrett, Hye-Jung Chun et al. "Reversion to an Embryonic Alternative Splicing Program Enhances Leukemia Stem Cell Self-Renewal". Blood 126, n. 23 (3 dicembre 2015): 1227. http://dx.doi.org/10.1182/blood.v126.23.1227.1227.

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Abstract Background Formative research suggests that a human embryonic stem cell-specific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. However, its role in malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs) had not been established. Methods Whole transcriptome RNA sequencing (RNA-seq) was performed on FACS purified progenitors from normal, chronic phase and blast crisis chronic myeloid leukemia samples and analyzed using Cuff-links, GSEA and IPA software. Splice isoform specific qRT-PCR, confocal microscopy, lentiviral overexpression and shRNA knockdown experiments were performed according to published methods (Jamieson NEJM 2004; Geron et al Cancer Cell 2008; Goff et al Cell Stem Cell 2013). Results We performed LSC RNA-seq, lentiviral overexpression and knockdown and discovered that decreased expression of MBNL3, a repressor of an embryonic alternative splicing program and reprogramming, activated a pluripotency network and increased expression of a pro-survival isoform of CD44v3, which is more commonly expressed in human embryonic stem cells. This resulted in malignant reprogramming of progenitors in blast crisis CML endowing them with unbridled survival and self-renewal capacity. This is the first description of MBNL3 downregulation as a mechanism of reversion to an embryonic alternative splicing program, which elicits malignant progenitor reprogramming of progenitors into self-renewing leukemia stem cells. While isoform specific lentiviral CD44v3 overexpression enhanced chronic phase CML progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. In keeping with activation of a stem cell reprogramming network, CD44v3 upregulation was associated with increased expression of pluripotency transcription factors, including OCT4, SOX2 and b-catenin in addition to the pro-survival long isoforms of MCL1 and BCLX resulting in increased self-renewal and apoptosis resistance. Conclusion In summary, MBNL3 downregulation activates an embryonic alternative splicing program, typified by CD44v3 overexpression, and represents a novel mechanism governing LSC generation in malignant microenvironments. Reversal of malignant reprogramming by epigenetic modulation of embryonic alternative splicing or via monoclonal antibody targeting of CD44v3 splice isoform may represent a pivotal opportunity for selective BC LSC eradication. Disclosures Jamieson: Johnson & Johnson: Research Funding; GlaxoSmithKline: Research Funding.

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Ihsan, M. O., D. M. Tan, U. Muniasamy, M. S. Ong, X. Y. Lin, C. N. Lee, R. Dorajoo e V. Sorokin. "Muscleblind-like (MBNL) protein family overexpression lead to pro-synthetic phenotype modulation of arterial human vascular smooth muscle cells in diabetes mellitus". Atherosclerosis 355 (agosto 2022): 205–6. http://dx.doi.org/10.1016/j.atherosclerosis.2022.06.821.

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22

Ju, Woong, Hye Youn Sung e Jung-Hyuck Ahn. "Abstract B091: Overexpression of Muscleblind Like Splicing Regulator 2 (MBNL2) enhances cisplatin resistance in ovarian cancer". Molecular Cancer Therapeutics 22, n. 12_Supplement (1 dicembre 2023): B091. http://dx.doi.org/10.1158/1535-7163.targ-23-b091.

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Abstract (sommario):

Abstract Ovarian cancer is the second most commonly diagnosed gynecological cancer and has the highest mortality rate of all gynecological cancers worldwide. Although cisplatin is one of the most effective antitumor drugs for ovarian cancer, the emergence of chemoresistance to cisplatin is a major barrier to successful therapy. To identify epigenetically regulated genes directly associated with ovarian cancer cisplatin resistance, we compared the expression and methylation profiles of cisplatin-sensitive and -resistant human ovarian cancer cell lines. We identified Muscleblind Like Splicing Regulator 2 (MBNL2) as one of the key candidate genes for cisplatin drug response. Interestingly, in cisplatin-resistant cell lines, MBNL2 mRNA expression was significantly upregulated, and the MBNL2 promoter was associated with hypomethylation of the specific cytosine-phosphate-guanine (CpG) sites. Reduced MBNL2 expression in cisplatin-sensitive cell lines was restored by treatment with a DNA demethylation agent, suggesting epigenetic regulation of MBNL2 expression by promoter methylation. Furthermore, depletion of MBNL2 in cisplatin-resistant cells induced cytotoxicity in response to cisplatin, whereas overexpression of MBNL2 in cisplatin-sensitive cells increased chemoresistance, indicating that MBNL2 plays a vital role in developing chemoresistance in ovarian cancer cells. Furthermore, we performed meta-analysis using fourteen publicly available datasets to assess the association between expression of MBNL2 and overall survival in patients with serous-type ovarian cancer. The pooled Hazard ratios (HRs) estimate was significantly greater than 1 for overall survival (HR=1.09, p-value=0.0034). The association was more significant (HR=1.12, p-value=0.001) when tumor stage was added to the survival analysis as a covariate. The meta-analysis revealed that high expression of MBNL2 was significantly associated with poor prognosis and a higher risk of death in ovarian cancer patients with serous tumor. Additionally, we further validated the MBNL2 mRNA expression in primary ovarian tumor tissues. The statistically significant upregulation of MBNL2 mRNA expression was observed in cisplatin-resistant patients compared to that of cisplatin-sensitive patients. Our findings suggest MBNL2 may be a potential therapeutic target for the prevention of chemoresistance to cisplatin in ovarian cancer. Citation Format: Woong Ju, Hye Youn Sung, Jung-Hyuck Ahn. Overexpression of Muscleblind Like Splicing Regulator 2 (MBNL2) enhances cisplatin resistance in ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B091.

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Chen, Jiaorong, Jiaqi Wang, Jingyi Qian, Mengying Bao, Xin Zhang e Zheng Huang. "MBNL1 Suppressed Cancer Metastatic of Skin Squamous Cell Carcinoma Via by TIAL1/MYOD1/Caspase-9/3 Signaling Pathways". Technology in Cancer Research & Treatment 20 (1 gennaio 2021): 153303382096075. http://dx.doi.org/10.1177/1533033820960755.

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Objective: The incidence of skin squamous cell carcinoma (SSCC) has recently been increasing, with diverse clinical manifestations.SSCC could metastasize to lymph nodes or other organs, posing a great threat to life. The present study was designed to investigate the function and underlying mechanism of muscleblind-like protein 1 (MBNL1) in skin squamous cell carcinoma. Methods: SCL-1 cell was used for vitro model and transfected with MBNL1 or siMBNL1 plasmids. MTT Assays, LDH activity ELISA, and Transwell chamber migration experiment were used to confirm the effects of MBNL1 on cell growth of SCL-1 cell. Western blot analysis was used to analyze the mechanism of MBNL1 in SCL-1 cell. Results: Down-regulation of MBNL1 promoted cell metastasis of SSCC, while up-regulation of MBNL1 reduced cell metastasis of SSCC in vitro. Down-regulation of MBNL1 suppressed the protein expression of T cell intracellular antigen (TIAL1), myogenic determinant 1 (MyoD1) and Caspase-3 in vitro. Consistent with these observations, inhibition of TIAL1 or MYOD1 expression attenuated the effects of MBNL1 in SSCC. Conclusion: The present study revealed that MBNL1 suppressed thecancer metastatic capacity of SSCC via by TIAL1/MYOD1/Caspase-3 signaling pathways.

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Tran, Hélène, Nathalie Gourrier, Camille Lemercier-Neuillet, Claire-Marie Dhaenens, Audrey Vautrin, Francisco José Fernandez-Gomez, Ludovic Arandel et al. "Analysis of Exonic Regions Involved in Nuclear Localization, Splicing Activity, and Dimerization of Muscleblind-like-1 Isoforms". Journal of Biological Chemistry 286, n. 18 (18 marzo 2011): 16435–46. http://dx.doi.org/10.1074/jbc.m110.194928.

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Muscleblind-like-1 (MBNL1) is a splicing regulatory factor controlling the fetal-to-adult alternative splicing transitions during vertebrate muscle development. Its capture by nuclear CUG expansions is one major cause for type 1 myotonic dystrophy (DM1). Alternative splicing produces MBNL1 isoforms that differ by the presence or absence of the exonic regions 3, 5, and 7. To understand better their respective roles and the consequences of the deregulation of their expression in DM1, here we studied the respective roles of MBNL1 alternative and constitutive exons. By combining genetics, molecular and cellular approaches, we found that (i) the exon 5 and 6 regions are both needed to control the nuclear localization of MBNL1; (ii) the exon 3 region strongly enhances the affinity of MBNL1 for its pre-mRNA target sites; (iii) the exon 3 and 6 regions are both required for the splicing regulatory activity, and this function is not enhanced by an exclusive nuclear localization of MBNL1; and finally (iv) the exon 7 region enhances MBNL1-MBNL1 dimerization properties. Consequently, the abnormally high inclusion of the exon 5 and 7 regions in DM1 is expected to enhance the potential of MBNL1 of being sequestered with nuclear CUG expansions, which provides new insight into DM1 pathophysiology.

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Cheng, Albert W., Jiahai Shi, Piu Wong, Katherine L. Luo, Paula Trepman, Eric T. Wang, Heejo Choi, Christopher B. Burge e Harvey F. Lodish. "Muscleblind-like 1 (Mbnl1) regulates pre-mRNA alternative splicing during terminal erythropoiesis". Blood 124, n. 4 (24 luglio 2014): 598–610. http://dx.doi.org/10.1182/blood-2013-12-542209.

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Sun, Xueqin, Xinghua Diao, Xiaolin Zhu, Xuexue Yin e Guangying Cheng. "Nanog-mediated stem cell properties are critical for MBNL3-associated paclitaxel resistance of ovarian cancer". Journal of Biochemistry 169, n. 6 (18 febbraio 2021): 747–56. http://dx.doi.org/10.1093/jb/mvab021.

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Abstract Paclitaxel (PTX) is the standard first-line treatment of ovarian cancer, but its efficacy is limited by multidrug resistance. Therefore, it is crucial to identify effective drug targets to facilitate PTX sensitivity for ovarian cancer treatment. Seventy PTX-administrated ovarian cancer patients were recruited in this study for gene expression and survival rate analyses. Muscleblind-like-3 (MBNL3) gain-of-function and loss-of-function experiments were carried out in ovarian cancer cells (parental and PTX-resistant) and xenograft model. Cancer cell viability, apoptosis, spheroids formation, Nanog gene silencing were examined and conducted to dissect the underlying mechanism of MBNL3-mediated PTX resistance. High expression of MBNL3 was positively correlated with PTX resistance and poor prognosis of ovarian cancer. MBNL3 increased cell viability and decreased apoptosis in ovarian stem-like cells, through upregulating Nanog. This study suggests the MBNL3-Nanog axis is a therapeutic target for the treatment of PTX resistance in ovarian cancer management.

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Gates, Devika P., Leslie A. Coonrod e J. Andrew Berglund. "Autoregulated Splicing of muscleblind-like 1 (MBNL1) Pre-mRNA". Journal of Biological Chemistry 286, n. 39 (9 agosto 2011): 34224–33. http://dx.doi.org/10.1074/jbc.m111.236547.

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28

Cai, Jin, Ningchao Wang, Guanglan Lin, Haowei Zhang, Weidong Xie, Yaou Zhang e Naihan Xu. "MBNL2 Regulates DNA Damage Response via Stabilizing p21". International Journal of Molecular Sciences 22, n. 2 (14 gennaio 2021): 783. http://dx.doi.org/10.3390/ijms22020783.

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Abstract (sommario):

RNA-binding proteins are frequently dysregulated in human cancer and able to modulate tumor cell proliferation as well as tumor metastasis through post-transcriptional regulation on target genes. Abnormal DNA damage response and repair mechanism are closely related to genome instability and cell transformation. Here, we explore the function of the RNA-binding protein muscleblind-like splicing regulator 2 (MBNL2) on tumor cell proliferation and DNA damage response. Transcriptome and gene expression analysis show that the PI3K/AKT pathway is enriched in MBNL2-depleted cells, and the expression of cyclin-dependent kinase inhibitor 1A (p21CDKN1A) is significantly affected after MBNL2 depletion. MBNL2 modulates the mRNA and protein levels of p21, which is independent of its canonical transcription factor p53. Moreover, depletion of MBNL2 increases the phosphorylation levels of checkpoint kinase 1 (Chk1) serine 345 (S345) and DNA damage response, and the effect of MBNL2 on DNA damage response is p21-dependent. MBNL2 would further alter tumor cell fate after DNA damage, MBNL2 knockdown inhibiting DNA damage repair and DNA damage-induced senescence, but promoting DNA damage-induced apoptosis.

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Li, Yanbing, Min Zong, Xiaonan Guan, Xuejiao Wu, Guiling Ma, Yu Wei e Zhi Li. "MBNL1-AS1 Promotes Hypoxia-Induced Myocardial Infarction via the miR-132-3p/RAB14/CAMTA1 Axis". Oxidative Medicine and Cellular Longevity 2023 (4 febbraio 2023): 1–12. http://dx.doi.org/10.1155/2023/3308725.

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Abstract (sommario):

Background. Mounting evidence have indicated that long noncoding RNA (lncRNA) muscleblind like splicing regulator 1 antisense RNA 1 (MBNL1-AS1) play a crucial regulatory role in cardiovascular disease, myocardial infarction (MI) included. In this research, we sought to probe into the biological function and potential mechanism of MBNL1-AS1 in MI. Methods. Cardiomyocytes were treated under hypoxic conditions for 0–12 h. Functional assays including CCK-8 and flow cytometry were performed to assess hypoxia-stimulated cardiomyocyte viability and apoptosis, respectively. Moreover, bioinformatics analysis and mechanical assays were conducted to reveal the competitive endogenous RNA (ceRNA) mechanism of MBNL1-AS1. Results. The upregulation of MBNL1-AS1 was found in hypoxia-stimulated cardiomyocytes. Functionally, the downregulation of MBNL1-AS1 dramatically promoted hypoxia-induced cardiomyocyte viability and inhibited apoptosis. Mechanistically, miR-132-3p bound to MBNL1-AS1 in hypoxia-induced cardiomyocytes, and miR-132-3p directly targeted RAB14, member RAS oncogene family (RAB14) and calmodulin binding transcription activator 1 (CAMTA1). Furthermore, MBNL1-AS1 upregulates the expression of RAB14 and CAMTA1 in hypoxia-stimulated cardiomyocytes via targeting miR-132-3p. Conclusions. The current study revealed the critical role of the MBNL1-AS1/miR-132-3p/RAB14/CAMTA1 axis in MI, indicating MBNL1-AS1 as an innovative therapeutic target for MI.

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Yokoyama, Shingo, Yoshitaka Ohno, Tatsuro Egawa, Kazuya Ohashi, Rika Ito, Huascar Pedro Ortuste Quiroga, Tomohiro Yamashita e Katsumasa Goto. "MBNL1-Associated Mitochondrial Dysfunction and Apoptosis in C2C12 Myotubes and Mouse Skeletal Muscle". International Journal of Molecular Sciences 21, n. 17 (2 settembre 2020): 6376. http://dx.doi.org/10.3390/ijms21176376.

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We explored the interrelationship between a tissue-specific alternative splicing factor muscleblind-like 1 (MBNL1) and peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α), B-cell lymphoma 2 (Bcl-2) or Bcl-2-associated X protein (Bax) in C2C12 myotubes and mouse skeletal muscle to investigate a possible physiological role of MBNL1 in mitochondrial-associated apoptosis of skeletal muscle. Expression level of PGC-1α and mitochondrial membrane potential evaluated by the fluorescence ratio of JC-1 aggregate to monomer in C2C12 myotubes were suppressed by knockdown of MBNL1. Conversely, the ratio of Bax to Bcl-2 as well as the apoptotic index in C2C12 myotubes was increased by MBNL1 knockdown. In plantaris muscle, on the other hand, not only the minimum muscle fiber diameter but also the expression level of MBNL1 and PGC-1α in of 100-week-old mice were significantly lower than that of 10-week-old mice. Furthermore, the ratio of Bax to Bcl-2 in mouse plantaris muscle was increased by aging. These results suggest that MBNL1 may play a key role in aging-associated muscle atrophy accompanied with mitochondrial dysfunction and apoptosis via mediating PGC-1α expression in skeletal muscle.

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Hao, Minqi, Kevan Akrami, Ke Wei, Carlos De Diego, Nam Che, Jeong-Hee Ku, James Tidball, Michael C. Graves, Perry B. Shieh e Fabian Chen. "Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy". Developmental Dynamics 237, n. 2 (21 gennaio 2008): 403–10. http://dx.doi.org/10.1002/dvdy.21428.

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Seachrist, Darcie D., Molly M. Hannigan, Natasha N. Ingles, Bryan M. Webb, Kristen L. Weber-Bonk, Peng Yu, Gurkan Bebek et al. "The transcriptional repressor BCL11A promotes breast cancer metastasis". Journal of Biological Chemistry 295, n. 33 (23 giugno 2020): 11707–19. http://dx.doi.org/10.1074/jbc.ra120.014018.

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Abstract (sommario):

The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Here, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-α6 (ITGA6), which is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing of ITGA6. Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.

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Teplova, Marianna, e Dinshaw J. Patel. "Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1". Nature Structural & Molecular Biology 15, n. 12 (30 novembre 2008): 1343–51. http://dx.doi.org/10.1038/nsmb.1519.

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34

Lee, Johanna E., e Thomas A. Cooper. "Pathogenic mechanisms of myotonic dystrophy". Biochemical Society Transactions 37, n. 6 (19 novembre 2009): 1281–86. http://dx.doi.org/10.1042/bst0371281.

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Abstract (sommario):

DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3′-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)n or (CCUG)n. The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.

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Ramon-Duaso, Carla, Thomas Gener, Marta Consegal, Cristina Fernández-Avilés, Juan José Gallego, Laura Castarlenas, Maurice S. Swanson et al. "Methylphenidate Attenuates the Cognitive and Mood Alterations Observed in Mbnl2 Knockout Mice and Reduces Microglia Overexpression". Cerebral Cortex 29, n. 7 (27 luglio 2018): 2978–97. http://dx.doi.org/10.1093/cercor/bhy164.

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Abstract Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting muscle and central nervous system (CNS) function. The cellular mechanisms underlying CNS alterations are poorly understood and no useful treatments exist for the neuropsychological deficits observed in DM1 patients. We investigated the progression of behavioral deficits present in male and female muscleblind-like 2 (Mbnl2) knockout (KO) mice, a rodent model of CNS alterations in DM1, and determined the biochemical and electrophysiological correlates in medial prefrontal cortex (mPFC), striatum and hippocampus (HPC). Male KO exhibited more cognitive impairment and depressive-like behavior than female KO mice. In the mPFC, KO mice showed an overexpression of proinflammatory microglia, increased transcriptional levels of Dat, Drd1, and Drd2, exacerbated dopamine levels, and abnormal neural spiking and oscillatory activities in the mPFC and HPC. Chronic treatment with methylphenidate (MPH) (1 and 3 mg/kg) reversed the behavioral deficits, reduced proinflammatory microglia in the mPFC, normalized prefrontal Dat and Drd2 gene expression, and increased Bdnf and Nrf2 mRNA levels. These findings unravel the mechanisms underlying the beneficial effects of MPH on cognitive deficits and depressive-like behaviors observed in Mbnl2 KO mice, and suggest that MPH could be a potential candidate to treat the CNS deficiencies in DM1 patients.

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Ballester-Lopez, Alfonsina, Judit Núñez-Manchón, Emma Koehorst, Ian Linares-Pardo, Miriam Almendrote, Giuseppe Lucente, Nicolau Guanyabens et al. "Three-dimensional imaging in myotonic dystrophy type 1". Neurology Genetics 6, n. 4 (21 luglio 2020): e484. http://dx.doi.org/10.1212/nxg.0000000000000484.

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Abstract (sommario):

ObjectiveWe aimed to determine whether 3D imaging reconstruction allows identifying molecular:clinical associations in myotonic dystrophy type 1 (DM1).MethodsWe obtained myoblasts from 6 patients with DM1 and 6 controls. We measured cytosine-thymine-guanine (CTG) expansion and detected RNA foci and muscleblind like 1 (MBNL1) through 3D reconstruction. We studied dystrophia myotonica protein kinase (DMPK) expression and splicing alterations of MBNL1, insulin receptor, and sarcoplasmic reticulum Ca(2+)-ATPase 1.ResultsThree-dimensional analysis showed that RNA foci (nuclear and/or cytoplasmic) were present in 45%–100% of DM1-derived myoblasts we studied (range: 0–6 foci per cell). RNA foci represented <0.6% of the total myoblast nuclear volume. CTG expansion size was associated with the number of RNA foci per myoblast (r = 0.876 [95% confidence interval 0.222–0.986]) as well as with the number of cytoplasmic RNA foci (r = 0.943 [0.559–0.994]). Although MBNL1 colocalized with RNA foci in all DM1 myoblast cell lines, colocalization only accounted for 1% of total MBNL1 expression, with the absence of DM1 alternative splicing patterns. The number of RNA foci was associated with DMPK expression (r = 0.967 [0.079–0.999]). On the other hand, the number of cytoplasmic RNA foci was correlated with the age at disease onset (r = −0.818 [−0.979 to 0.019]).ConclusionsCTG expansion size modulates RNA foci number in myoblasts derived from patients with DM1. MBNL1 sequestration plays only a minor role in the pathobiology of the disease in these cells. Higher number of cytoplasmic RNA foci is related to an early onset of the disease, a finding that should be corroborated in future studies.

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Smith, Kelly P., Meg Byron, Carol Johnson, Yigong Xing e Jeanne B. Lawrence. "Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains". Journal of Cell Biology 178, n. 6 (10 settembre 2007): 951–64. http://dx.doi.org/10.1083/jcb.200706048.

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Abstract (sommario):

In myotonic dystrophy type 1 (DM1), triplet repeat expansion in the 3′ untranslated region of dystrophia myotonica protein kinase (DMPK) causes the nuclear retention of mutant messenger RNA (mRNA). Although the DMPK gene locus positions precisely at the outer edge of a factor-rich SC-35 domain, the normal mRNA consistently accumulates within the domain, and this RNA is depleted upon transcriptional inhibition. In DM1, mutant transcripts detach from the gene but accumulate in granules that abut but do not enter SC-35 domains, suggesting that RNA entry into the domain is blocked. Despite their exclusion from these compartments, mutant transcripts are spliced. MBNL1 (muscleblind-like protein 1) is an alternative splicing factor that becomes highly concentrated with mutant RNA foci. Small interfering RNA–mediated knockdown of MBNL1 promotes the accumulation or entry of newly synthesized mutant transcripts in the SC-35 domain. Collectively, these data suggest that an initial step in the intranuclear path of some mRNAs is passage from the gene into an SC-35 domain and implicate these structures in postsplicing steps before export.

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Herrendorff, Ruben, Maria Teresa Faleschini, Adeline Stiefvater, Beat Erne, Tatiana Wiktorowicz, Frances Kern, Matthias Hamburger, Olivier Potterat, Jochen Kinter e Michael Sinnreich. "Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I". Journal of Biological Chemistry 291, n. 33 (13 giugno 2016): 17165–77. http://dx.doi.org/10.1074/jbc.m115.710616.

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Abstract (sommario):

Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3′ UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases.

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Neault, Nafisa, Aymeric Ravel-Chapuis, Stephen D. Baird, John A. Lunde, Mathieu Poirier, Emiliyan Staykov, Julio Plaza-Diaz et al. "Vorinostat Improves Myotonic Dystrophy Type 1 Splicing Abnormalities in DM1 Muscle Cell Lines and Skeletal Muscle from a DM1 Mouse Model". International Journal of Molecular Sciences 24, n. 4 (14 febbraio 2023): 3794. http://dx.doi.org/10.3390/ijms24043794.

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Abstract (sommario):

Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1, rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDA-approved drug library, we have screened for a reduction of CUG foci in patient muscle cells and identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) spliceopathy was also improved by vorinostat treatment. Vorinostat treatment in a mouse model of DM1 (human skeletal actin–long repeat; HSALR) improved several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease markers marks vorinostat as a promising novel DM1 therapy.

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Lee, Kyung-Soon, Yi Cao, Hanna E. Witwicka, Susan Tom, Stephen J. Tapscott e Edith H. Wang. "RNA-binding Protein Muscleblind-like 3 (MBNL3) Disrupts Myocyte Enhancer Factor 2 (Mef2) β-Exon Splicing". Journal of Biological Chemistry 285, n. 44 (13 agosto 2010): 33779–87. http://dx.doi.org/10.1074/jbc.m110.124255.

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Neault, Nafisa, Sean O’Reilly, Aiman Tariq Baig, Julio Plaza-Diaz, Mehrdad Azimi, Faraz Farooq, Stephen D. Baird e Alex MacKenzie. "High-throughput kinome-RNAi screen identifies protein kinase R activator (PACT) as a novel genetic modifier of CUG foci integrity in myotonic dystrophy type 1 (DM1)". PLOS ONE 16, n. 9 (14 settembre 2021): e0256276. http://dx.doi.org/10.1371/journal.pone.0256276.

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Abstract (sommario):

Myotonic Dystrophy Type 1 (DM1) is the most common form of adult muscular dystrophy (~1:8000). In DM1, expansion of CTG trinucleotide repeats in the 3’ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene results in DMPK mRNA hairpin structures which aggregate as insoluble ribonuclear foci and sequester several RNA-binding proteins. The resulting sequestration and misregulation of important splicing factors, such as muscleblind-like 1 (MBNL1), causes the aberrant expression of fetal transcripts for several genes that contribute to the disease phenotype. Previous work has shown that antisense oligonucleotide-mediated disaggregation of the intranuclear foci has the potential to reverse downstream anomalies. To explore whether the nuclear foci are, to some extent, controlled by cell signalling pathways, we have performed a screen using a small interfering RNA (siRNA) library targeting 518 protein kinases to look at kinomic modulation of foci integrity. RNA foci were visualized by in situ hybridization of a fluorescent-tagged (CAG)10 probe directed towards the expanded DMPK mRNA and the cross-sectional area and number of foci per nuclei were recorded. From our screen, we have identified PACT (protein kinase R (PKR) activator) as a novel modulator of foci integrity and have shown that PACT knockdown can both increase MBNL1 protein levels; however, these changes are not suffcient for significant correction of downstream spliceopathies.

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Gurunathan, Arun, Lana S. Itskovich, Jason Clark, Matthew Burwinkel, Nathan Salomonis, Meenakshi Venkatasubramanian, Kashish Chetal, Lynn Lee e Ashish R. Kumar. "MLL-Fusion Leukemia Dependence on MBNL1 Is Associated with Alternative Splicing of Oncogenic Proteins". Blood 132, Supplement 1 (29 novembre 2018): 3883. http://dx.doi.org/10.1182/blood-2018-99-112349.

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Abstract Leukemia is the most common childhood cancer, and while outcomes for most children have improved significantly, the prognosis in infant leukemia remains dire. The majority of infant leukemia, either acute myeloid (AML) or acute lymphoid (ALL), is caused by reciprocal translocations of the MLL-gene. Prior studies show that one of the most consistently overexpressed genes in these leukemias (compared to all other leukemias) is the RNA binding protein muscleblind-like 1 (MBNL1). We found that MBNL1 knockdown significantly impairs propagation of MLL-rearranged (MLLr) leukemic cells in vitro and in vivo using human cell lines and transformed murine cells. To further characterize the role of MBNL1 in acute leukemia, we performed shRNA knockdown experiments in MLLr and non-MLLr leukemia cell lines and in primary patient samples. While MBNL1 knockdown does also impair growth of non-MLLr leukemic cells, the effect is less pronounced. In a 5-day growth experiment MBNL1-knockdown MLLr cells (THP-1) displayed a median 71% reduced growth compared to controls, whereas non-MLLr cells (HL-60) displayed only a median 32% growth reduction (p=0.0001). Cells from two patients with MLLr AML (one with MLL-AF9 and one with MLL-AF10 fusion) underwent shNT (non-targeting) or shMBNL1 transduction.. Unsorted cells were transplanted into NSGS mice. Mice were observed until showing signs of distress and then analyzed for engraftment of human cells and abundance of transduced cells (venus-positive). In the shNT group there was robust persistence of transduced cells (7%-98% of human cells), whereas shMBNL1-transduced cells were not detected or comprised <1% of human cells in most of the recipient mice. Given that MBNL1 is known to regulate alternative splicing, we used unbiased RNAseq along with a novel analytic splice-junction and intron-quantification toolkit (AltAnalyze) to determine splicing changes induced by knockdown of MBNL1 in the MLLr leukemia cell line MOLM-13. In a parallel analysis, we determined splicing differences between MLLr and cytogenetically-normal (CN) AML patient samples. We then compared these two results to determine the splicing events regulated by MBNL1 and assess the contribution of MBNL1 to splicing events observed in primary MLLr leukemias. Strikingly, this comparative analysis found that 88% of overlapping differentially expressed splicing events (75 out of 85) were concordant between patient MLLr and CN-AML as compared to control versus MBNL1 knockdown. The most common class of splicing event that occurred with MBNL1 knockdown was intron retention. Specifically, our findings suggest that MBNL1 knockdown restores intron retention, and that MBNL1 overexpression promotes expression of protein-coding genes that would otherwise be suppressed through intron retention-introduced premature termination codons. Several genes whose transcripts are alternatively spliced by MBNL1 have prior associations with cancer, most notably DOT1L and SETD1A which are specifically implicated in MLLr leukemia. Splicing validation through RT-PCR confirmed increased intron retention in DOT1L and SETD1A transcripts after MBNL1 knockdown. Interestingly, one target of MBNL1 is the MBNL1 mRNA itself, with resultant exclusion of exon 5. MBNL1 lacking exon 5 has a stronger affinity to RNA. In summary, our data suggests that MBNL1 plays a key role in the pathogenesis of MLL-fusion leukemia, wherein it stabilizes the transcripts of multiple leukemogenic genes including DOT1L and SETD1A. Proteins such as DOT1L are critical for transcriptional activation of downstream targets of the MLL-fusion protein (including activation of MBNL1, creating a positive feedback loop). Additionally, high levels of MBNL1 protein may alter splicing in ways that enhance MBNL1 functionality. Disclosures No relevant conflicts of interest to declare.

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Itskovich, Svetlana S., Jason Clark, James C. Mulloy, Matthew D. Disney e Ashish R. Kumar. "MBNL1 As a New Therapeutic Target in MLL-Fusion Gene Leukemia". Blood 126, n. 23 (3 dicembre 2015): 462. http://dx.doi.org/10.1182/blood.v126.23.462.462.

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Abstract Translocations of the Mixed Lineage Leukemia (MLL) gene located on chromosome 11 are commonly found in infants with AML or ALL and in secondary leukemia at all ages. A majority of patients with these translocations have a poor prognosis. Gene expression profiling studies demonstrate that one of the most consistently overexpressed genes in these leukemias (compared to all other leukemias) is muscleblind-like 1 (MBNL1). Further, MBNL1 was also identified as a direct transcriptional target of MLL-fusion proteins. An RNA-binding protein, MBNL1 is known to be a key factor in the pathophysiology of Myotonic Dystrophy Type I (DM), where sequestration of MBNL1 leads to splicing defects in muscle and neuronal cells. However, the role of MBNL1 in hematopoiesis and leukemogenesis is unknown. To determine the role of MBNL1 in normal hematopoiesis we studied MBNL1-/- mice. Compared to littermate controls, MBNL1-/- mice showed no differences in peripheral blood counts or bone marrow cellularity. When challenged with 5-FU, both MBNL1-/- and wild type mice displayed similar kinetics of peripheral blood cytopenia and recovery. Next we examined the role of MBNL1 in hematopoietic stem cell function using a competitive transplantation assay. Lethally irradiated mice were transplanted with a 1:1 mix of CD45.1 and CD45.2 bone marrow, with the latter being wild-type or MBNL1-/-. Flow cytometry analysis of peripheral blood at 4 weeks post-transplant showed donor chimerism being 53±4.14% in recipients of wild type marrow and 25±5.41 % in the MBNL1-/- recipients. Successive analyses every 4 weeks showed the chimerism to be stable over the next 16 weeks. To determine the role of MBNL1 in leukemia, we transformed MBNL1-/- or wild type bone marrow cells with various oncogenes delivered via retroviral transduction and compared them in methylcellulose colony replating assays. Absence of MBNL1 significantly reduced colony formation in MLL-AF9 and E2A-HLF transformed cells by 59.5% (± 27.1) and 50.7% (± 23) respectively, compared to controls. To assess the role of MBNL1 in leukemia in vivo, we transplanted MLL-AF9-transformed wild type or MBNL1-/- cells into irradiated mice. All recipients injected with wild-type MLL-AF9-transformed cells succumbed to leukemia with a median time of 106 days. In contrast, the majority of recipients of MBNL1-/- cells survived leukemia-free for at least 140 days post-transplantation (p=0.0017, log rank test). We next assessed the role of MBNL1 in human leukemia cells. Lentiviral-shRNA knockdown of MBNL1 in leukemia cell lines (MV4;11, THP-1) significantly inhibited cell growth, both in liquid culture and methylcellulose colony forming assays. To determine the requirement of MBNL1 for leukemia propagation in vivo, we used cord blood-derived leukemia cells bearing the MLL-AF9 fusion gene and mutant NRAS (MA9NRAS). MA9NRAS cells transduced with MBNL1-specific or control (non-targeting, NT) shRNA were transplanted into immunodeficient mice. Six weeks after transplant, bone marrow aspirates showed persistence of lentiviral-transduced cells in 85% of the NT-group. On the other hand, MBNL1-shRNA transduced cells were not detected in any of the recipient mice. These results suggest that MBNL1 is essential for leukemia cell propagation in vivo. Finally, we tested therapeutic targeting of MBNL1 in MLL-fusion gene leukemia. A lead inhibitor that prevents binding of MBNL1 to its targets was recently identified. Treatment of MA9NRAS cells with the inhibitor for 48 hours led to significant apoptosis whereas normal cord blood CD34+ cells were relatively less sensitive. Blockade of MBNL1 in leukemia cells either by shRNA-knockdown or by the inhibitor showed identical changes in splicing patterns of known MBNL1 target genes. Collectively, our data suggest that MBNL1 is required for the initiation and propagation of MLL-fusion gene leukemia while it appears relatively dispensable for normal hematopoiesis. Further, we have identified a promising lead inhibitor that could be developed for novel treatments for therapy-resistant leukemias. Disclosures No relevant conflicts of interest to declare.

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Angelbello, Alicia J., Suzanne G. Rzuczek, Kendra K. Mckee, Jonathan L. Chen, Hailey Olafson, Michael D. Cameron, Walter N. Moss, Eric T. Wang e Matthew D. Disney. "Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model". Proceedings of the National Academy of Sciences 116, n. 16 (29 marzo 2019): 7799–804. http://dx.doi.org/10.1073/pnas.1901484116.

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Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG)exp. The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG)exp has been targeted by antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer small molecule, Cugamycin, that recognizes the structure of r(CUG)exp and cleaves it in both DM1 patient-derived myotubes and a DM1 mouse model, leaving short repeats of r(CUG) untouched. In contrast, oligonucleotides that recognize r(CUG) sequence rather than structure cleave both long and short r(CUG)-containing transcripts. Transcriptomic, histological, and phenotypic studies demonstrate that Cugamycin broadly and specifically relieves DM1-associated defects in vivo without detectable off-targets. Thus, small molecules that bind and cleave RNA have utility as lead chemical probes and medicines and can selectively target disease-causing RNA structures to broadly improve defects in preclinical animal models.

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Sen, Supriya, Indrani Talukdar, Ying Liu, Joseph Tam, Sita Reddy e Nicholas J. G. Webster. "Muscleblind-like 1 (Mbnl1) Promotes Insulin Receptor Exon 11 Inclusion via Binding to a Downstream Evolutionarily Conserved Intronic Enhancer". Journal of Biological Chemistry 285, n. 33 (2 giugno 2010): 25426–37. http://dx.doi.org/10.1074/jbc.m109.095224.

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deLorimier, Elaine, Melissa N. Hinman, Jeremy Copperman, Kausiki Datta, Marina Guenza e J. Andrew Berglund. "Pseudouridine Modification Inhibits Muscleblind-like 1 (MBNL1) Binding to CCUG Repeats and Minimally Structured RNA through Reduced RNA Flexibility". Journal of Biological Chemistry 292, n. 10 (27 gennaio 2017): 4350–57. http://dx.doi.org/10.1074/jbc.m116.770768.

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Lueck, John D., Ami Mankodi, Maurice S. Swanson, Charles A. Thornton e Robert T. Dirksen. "Muscle Chloride Channel Dysfunction in Two Mouse Models of Myotonic Dystrophy". Journal of General Physiology 129, n. 1 (11 dicembre 2006): 79–94. http://dx.doi.org/10.1085/jgp.200609635.

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Muscle degeneration and myotonia are clinical hallmarks of myotonic dystrophy type 1 (DM1), a multisystemic disorder caused by a CTG repeat expansion in the 3′ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Transgenic mice engineered to express mRNA with expanded (CUG)250 repeats (HSALR mice) exhibit prominent myotonia and altered splicing of muscle chloride channel gene (Clcn1) transcripts. We used whole-cell patch clamp recordings and nonstationary noise analysis to compare and biophysically characterize the magnitude, kinetics, voltage dependence, and single channel properties of the skeletal muscle chloride channel (ClC-1) in individual flexor digitorum brevis (FDB) muscle fibers isolated from 1–3-wk-old wild-type and HSALR mice. The results indicate that peak ClC-1 current density at −140 mV is reduced >70% (−48.5 ± 3.6 and −14.0 ± 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 18–20- d-old HSALR mice. Nonstationary noise analysis revealed that the reduction in ClC-1 current density in HSALR FDB fibers results from a large reduction in ClC-1 channel density (170 ± 21 and 58 ± 11 channels/pF in control and HSALR fibers, respectively) and a modest decrease in maximal channel open probability(0.91 ± 0.01 and 0.75 ± 0.03, respectively). Qualitatively similar results were observed for ClC-1 channel activity in knockout mice for muscleblind-like 1 (Mbnl1ΔE3/ΔE3), a second murine model of DM1 that exhibits prominent myotonia and altered Clcn1 splicing (Kanadia et al., 2003). These results support a molecular mechanism for myotonia in DM1 in which a reduction in both the number of functional sarcolemmal ClC-1 and maximal channel open probability, as well as an acceleration in the kinetics of channel deactivation, results from CUG repeat–containing mRNA molecules sequestering Mbnl1 proteins required for proper CLCN1 pre-mRNA splicing and chloride channel function.

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Liu, Weifeng, Wenyuan Lin e Liangliang Yu. "Long non-coding RNA muscleblind like splicing regulator 1 antisense RNA 1 (LncRNA MBNL1-AS1) promotes the progression of acute myocardial infarction by regulating the microRNA-132-3p/SRY-related high-mobility-group box 4 (SOX4) axis". Bioengineered 13, n. 1 (1 gennaio 2022): 1424–35. http://dx.doi.org/10.1080/21655979.2021.2018974.

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Frison-Roche, Charles, Célia Martin Demier, Steve Cottin, Jeanne Lainé, Ludovic Arandel, Marius Halliez, Mégane Lemaitre et al. "MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination". Brain, 26 ottobre 2024. http://dx.doi.org/10.1093/brain/awae336.

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Abstract Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of Myotonic Dystrophy type 1 (DM1). In DM1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease. While attention to MBNL proteins has focused on their functions in skeletal muscle, new evidence suggests that their importance extends to motor neurons (MNs), pivotal cellular components in the control of motor skills and movement. To address this question, we generated conditional double knockout mice in which Mbnl1 and Mbnl2 were specifically deleted in motor neurons (MN-dKO). Adult MN-dKO mice develop gait coordination deficits associated with structural and ultrastructural defects in the neuromuscular junction, indicating that MBNL activity in MNs is crucial for the maintenance of the neuromuscular junction. In addition, transcriptome analysis performed on the spinal cord of MN-dKO mice identified mis-splicing events in genes associated with synaptic transmission and neuromuscular junction homeostasis. In summary, our results highlight the complex roles and regulatory mechanisms of MBNL proteins in MNs for muscle function and locomotion. This work provides valuable insights into fundamental aspects of RNA biology and offers promising avenues for therapeutic intervention in DM1 as well as a range of diseases associated with RNA dysregulation.

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Hildebrandt, Ryan P., Kathryn R. Moss, Aleksandra Janusz-Kaminska, Luke A. Knudson, Lance T. Denes, Tanvi Saxena, Devi Prasad Boggupalli et al. "Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes". Nature Communications 14, n. 1 (9 giugno 2023). http://dx.doi.org/10.1038/s41467-023-38923-6.

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AbstractRNA binding proteins (RBPs) act as critical facilitators of spatially regulated gene expression. Muscleblind-like (MBNL) proteins, implicated in myotonic dystrophy and cancer, localize RNAs to myoblast membranes and neurites through unknown mechanisms. We find that MBNL forms motile and anchored granules in neurons and myoblasts, and selectively associates with kinesins Kif1bα and Kif1c through its zinc finger (ZnF) domains. Other RBPs with similar ZnFs associate with these kinesins, implicating a motor-RBP specificity code. MBNL and kinesin perturbation leads to widespread mRNA mis-localization, including depletion of Nucleolin transcripts from neurites. Live cell imaging and fractionation reveal that the unstructured carboxy-terminal tail of MBNL1 allows for anchoring at membranes. An approach, termed RBP Module Recruitment and Imaging (RBP-MRI), reconstitutes kinesin- and membrane-recruitment functions using MBNL-MS2 coat protein fusions. Our findings decouple kinesin association, RNA binding, and membrane anchoring functions of MBNL while establishing general strategies for studying multi-functional, modular domains of RBPs.

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