IDEAS home Printed from https://ideas.repec.org/a/plo/pgen00/1006316.html
   My bibliography  Save this article

Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy

Author

Listed:
  • Stacey D Wagner
  • Adam J Struck
  • Riti Gupta
  • Dylan R Farnsworth
  • Amy E Mahady
  • Katy Eichinger
  • Charles A Thornton
  • Eric T Wang
  • J Andrew Berglund

Abstract

Alternative splicing is a regulated process that results in expression of specific mRNA and protein isoforms. Alternative splicing factors determine the relative abundance of each isoform. Here we focus on MBNL1, a splicing factor misregulated in the disease myotonic dystrophy. By altering the concentration of MBNL1 in cells across a broad dynamic range, we show that different splicing events require different amounts of MBNL1 for half-maximal response, and respond more or less steeply to MBNL1. Motifs around MBNL1 exon 5 were studied to assess how cis-elements mediate the MBNL1 dose-dependent splicing response. A framework was developed to estimate MBNL concentration using splicing responses alone, validated in the cell-based model, and applied to myotonic dystrophy patient muscle. Using this framework, we evaluated the ability of individual and combinations of splicing events to predict functional MBNL concentration in human biopsies, as well as their performance as biomarkers to assay mild, moderate, and severe cases of DM.Author Summary: Our studies provide insight into the mechanisms of myotonic dystrophy, the most common adult form of muscular dystrophy. In this disease, a family of RNA binding proteins is sequestered by toxic RNA, which leads to mis-regulation and disease symptoms. We have created a cellular model with one of these family members to study how these RNA binding proteins function in the absence of the toxic RNA. In parallel, we analyzed transcriptomic data from over 50 individuals (44 affected by myotonic dystrophy) with a range of disease severity. The results from the transcriptomic data provide a rational approach to select biomarkers for clinical research and therapeutic trials.

Suggested Citation

  • Stacey D Wagner & Adam J Struck & Riti Gupta & Dylan R Farnsworth & Amy E Mahady & Katy Eichinger & Charles A Thornton & Eric T Wang & J Andrew Berglund, 2016. "Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy," PLOS Genetics, Public Library of Science, vol. 12(9), pages 1-24, September.
  • Handle: RePEc:plo:pgen00:1006316
    DOI: 10.1371/journal.pgen.1006316
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006316
    Download Restriction: no

    File URL: https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006316&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pgen.1006316?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Eric T. Wang & Rickard Sandberg & Shujun Luo & Irina Khrebtukova & Lu Zhang & Christine Mayr & Stephen F. Kingsmore & Gary P. Schroth & Christopher B. Burge, 2008. "Alternative isoform regulation in human tissue transcriptomes," Nature, Nature, vol. 456(7221), pages 470-476, November.
    2. Hong Han & Manuel Irimia & P. Joel Ross & Hoon-Ki Sung & Babak Alipanahi & Laurent David & Azadeh Golipour & Mathieu Gabut & Iacovos P. Michael & Emil N. Nachman & Eric Wang & Dan Trcka & Tadeo Thomps, 2013. "MBNL proteins repress ES-cell-specific alternative splicing and reprogramming," Nature, Nature, vol. 498(7453), pages 241-245, June.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Ryan P. Hildebrandt & Kathryn R. Moss & Aleksandra Janusz-Kaminska & Luke A. Knudson & Lance T. Denes & Tanvi Saxena & Devi Prasad Boggupalli & Zhuangyue Li & Kun Lin & Gary J. Bassell & Eric T. Wang, 2023. "Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Ningyan Hu & Eunjoo Kim & Layal Antoury & Thurman M. Wheeler, 2023. "Correction of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Jean-Philippe Leduc-Gaudet & Anais Franco-Romero & Marina Cefis & Alaa Moamer & Felipe E. Broering & Giulia Milan & Roberta Sartori & Tomer Jordi Chaffer & Maude Dulac & Vincent Marcangeli & Dominique, 2023. "MYTHO is a novel regulator of skeletal muscle autophagy and integrity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Gustavo Glusman & Juan Caballero & Max Robinson & Burak Kutlu & Leroy Hood, 2013. "Optimal Scaling of Digital Transcriptomes," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-12, November.
    2. Xiaohong Li & Guy N Brock & Eric C Rouchka & Nigel G F Cooper & Dongfeng Wu & Timothy E O’Toole & Ryan S Gill & Abdallah M Eteleeb & Liz O’Brien & Shesh N Rai, 2017. "A comparison of per sample global scaling and per gene normalization methods for differential expression analysis of RNA-seq data," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-22, May.
    3. Jun Inamo & Akari Suzuki & Mahoko Takahashi Ueda & Kensuke Yamaguchi & Hiroshi Nishida & Katsuya Suzuki & Yuko Kaneko & Tsutomu Takeuchi & Hiroaki Hatano & Kazuyoshi Ishigaki & Yasushi Ishihama & Kazu, 2024. "Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Feng Wang & Yang Xu & Robert Wang & Beatrice Zhang & Noah Smith & Amber Notaro & Samantha Gaerlan & Eric Kutschera & Kathryn E. Kadash-Edmondson & Yi Xing & Lan Lin, 2023. "TEQUILA-seq: a versatile and low-cost method for targeted long-read RNA sequencing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Elizabeth A. Werren & Geneva R. LaForce & Anshika Srivastava & Delia R. Perillo & Shaokun Li & Katherine Johnson & Safa Baris & Brandon Berger & Samantha L. Regan & Christian D. Pfennig & Sonja Munnik, 2024. "TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    6. Patricia González-Rodríguez & Daniel J. Klionsky & Bertrand Joseph, 2022. "Autophagy regulation by RNA alternative splicing and implications in human diseases," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Miklos Csuros & Igor B Rogozin & Eugene V Koonin, 2011. "A Detailed History of Intron-rich Eukaryotic Ancestors Inferred from a Global Survey of 100 Complete Genomes," PLOS Computational Biology, Public Library of Science, vol. 7(9), pages 1-9, September.
    8. Nysia I George & John F Bowyer & Nathaniel M Crabtree & Ching-Wei Chang, 2015. "An Iterative Leave-One-Out Approach to Outlier Detection in RNA-Seq Data," PLOS ONE, Public Library of Science, vol. 10(6), pages 1-10, June.
    9. Ilias Georgakopoulos-Soares & Guillermo E. Parada & Hei Yuen Wong & Ragini Medhi & Giulia Furlan & Roberto Munita & Eric A. Miska & Chun Kit Kwok & Martin Hemberg, 2022. "Alternative splicing modulation by G-quadruplexes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Areum Han & Peter Stoilov & Anthony J Linares & Yu Zhou & Xiang-Dong Fu & Douglas L Black, 2014. "De Novo Prediction of PTBP1 Binding and Splicing Targets Reveals Unexpected Features of Its RNA Recognition and Function," PLOS Computational Biology, Public Library of Science, vol. 10(1), pages 1-18, January.
    11. Judith A Potashkin & Jose A Santiago & Bernard M Ravina & Arthur Watts & Alexey A Leontovich, 2012. "Biosignatures for Parkinson’s Disease and Atypical Parkinsonian Disorders Patients," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-13, August.
    12. Jiang Lin & Jing Yang & Xiang-mei Wen & Lei Yang & Zhao-qun Deng & Zhen Qian & Ji-chun Ma & Hong Guo & Ying-ying Zhang & Wei Qian & Jun Qian, 2014. "Detection of SRSF2-P95 Mutation by High-Resolution Melting Curve Analysis and Its Effect on Prognosis in Myelodysplastic Syndrome," PLOS ONE, Public Library of Science, vol. 9(12), pages 1-12, December.
    13. Wei Hu & Yangjun Wu & Qili Shi & Jingni Wu & Deping Kong & Xiaohua Wu & Xianghuo He & Teng Liu & Shengli Li, 2022. "Systematic characterization of cancer transcriptome at transcript resolution," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    14. Jianfei Hu & Eli Boritz & William Wylie & Daniel C Douek, 2017. "Stochastic principles governing alternative splicing of RNA," PLOS Computational Biology, Public Library of Science, vol. 13(9), pages 1-20, September.
    15. Hillary M. Heiling & Douglas R. Wilson & Naim U. Rashid & Wei Sun & Joseph G. Ibrahim, 2023. "Estimating cell type composition using isoform expression one gene at a time," Biometrics, The International Biometric Society, vol. 79(2), pages 854-865, June.
    16. Zhiyi Qin & Xuegong Zhang, 2017. "The identification of switch-like alternative splicing exons among multiple samples with RNA-Seq data," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-12, May.
    17. Marine Pesson & Alain Volant & Arnaud Uguen & Kilian Trillet & Pierre De La Grange & Marc Aubry & Mélanie Daoulas & Michel Robaszkiewicz & Gérald Le Gac & Alain Morel & Brigitte Simon & Laurent Corcos, 2014. "A Gene Expression and Pre-mRNA Splicing Signature That Marks the Adenoma-Adenocarcinoma Progression in Colorectal Cancer," PLOS ONE, Public Library of Science, vol. 9(2), pages 1-13, February.
    18. Donna K Slonim & Itai Yanai, 2009. "Getting Started in Gene Expression Microarray Analysis," PLOS Computational Biology, Public Library of Science, vol. 5(10), pages 1-4, October.
    19. Arashdeep Singh & Arati Rajeevan & Vishaka Gopalan & Piyush Agrawal & Chi-Ping Day & Sridhar Hannenhalli, 2022. "Broad misappropriation of developmental splicing profile by cancer in multiple organs," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. Seungjae Lee & Yen-Chung Chen & Austin E. Gillen & J. Matthew Taliaferro & Bart Deplancke & Hongjie Li & Eric C. Lai, 2022. "Diverse cell-specific patterns of alternative polyadenylation in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pgen00:1006316. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosgenetics (email available below). General contact details of provider: https://journals.plos.org/plosgenetics/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.