IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38273-3.html
   My bibliography  Save this article

Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching

Author

Listed:
  • Jennine M. Dawicki-McKenna

    (University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia)

  • Alex J. Felix

    (University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia)

  • Elisa A. Waxman

    (University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia)

  • Congsheng Cheng

    (Children’s Hospital of Philadelphia)

  • Defne A. Amado

    (Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine)

  • Paul T. Ranum

    (Children’s Hospital of Philadelphia)

  • Alexey Bogush

    (University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia)

  • Lea V. Dungan

    (University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia)

  • Jean Ann Maguire

    (Children’s Hospital of Philadelphia)

  • Alyssa L. Gagne

    (Children’s Hospital of Philadelphia)

  • Elizabeth A. Heller

    (University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine)

  • Deborah L. French

    (University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine)

  • Beverly L. Davidson

    (University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine)

  • Benjamin L. Prosser

    (University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia)

Abstract

Alternative splicing of neuronal genes is controlled partly by the coordinated action of polypyrimidine tract binding proteins (PTBPs). While PTBP1 is ubiquitously expressed, PTBP2 is predominantly neuronal. Here, we define the PTBP2 footprint in the human transcriptome using brain tissue and human induced pluripotent stem cell-derived neurons (iPSC-neurons). We map PTBP2 binding sites, characterize PTBP2-dependent alternative splicing events, and identify novel PTBP2 targets including SYNGAP1, a synaptic gene whose loss-of-function leads to a complex neurodevelopmental disorder. We find that PTBP2 binding to SYNGAP1 mRNA promotes alternative splicing and nonsense-mediated decay, and that antisense oligonucleotides (ASOs) that disrupt PTBP binding redirect splicing and increase SYNGAP1 mRNA and protein expression. In SYNGAP1 haploinsufficient iPSC-neurons generated from two patients, we show that PTBP2-targeting ASOs partially restore SYNGAP1 expression. Our data comprehensively map PTBP2-dependent alternative splicing in human neurons and cerebral cortex, guiding development of novel therapeutic tools to benefit neurodevelopmental disorders.

Suggested Citation

  • Jennine M. Dawicki-McKenna & Alex J. Felix & Elisa A. Waxman & Congsheng Cheng & Defne A. Amado & Paul T. Ranum & Alexey Bogush & Lea V. Dungan & Jean Ann Maguire & Alyssa L. Gagne & Elizabeth A. Hell, 2023. "Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38273-3
    DOI: 10.1038/s41467-023-38273-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38273-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-38273-3?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. 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.
    2. Sebastien M. Weyn-Vanhentenryck & Huijuan Feng & Dmytro Ustianenko & Rachel Duffié & Qinghong Yan & Martin Jacko & Jose C. Martinez & Marianne Goodwin & Xuegong Zhang & Ulrich Hengst & Stavros Lomvard, 2018. "Precise temporal regulation of alternative splicing during neural development," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    3. Michael Zabolocki & Kasandra McCormack & Mark Hurk & Bridget Milky & Andrew P. Shoubridge & Robert Adams & Jenne Tran & Anita Mahadevan-Jansen & Philipp Reineck & Jacob Thomas & Mark R. Hutchinson & C, 2020. "BrainPhys neuronal medium optimized for imaging and optogenetics in vitro," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    4. Kian Huat Lim & Zhou Han & Hyun Yong Jeon & Jacob Kach & Enxuan Jing & Sebastien Weyn-Vanhentenryck & Mikaela Downs & Anna Corrionero & Raymond Oh & Juergen Scharner & Aditya Venkatesh & Sophina Ji & , 2020. "Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    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. Yang Cao & Huachun Liu & Shannon S. Lu & Krysten A. Jones & Anitha P. Govind & Okunola Jeyifous & Christine Q. Simmons & Negar Tabatabaei & William N. Green & Jimmy. L. Holder & Soroush Tahmasebi & Al, 2023. "RNA-based translation activators for targeted gene upregulation," Nature Communications, Nature, vol. 14(1), pages 1-12, 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. Ya′nan Zhu & Jing He & Jiawen Wang & Wei Guo & Hongran Liu & Zhuoran Song & Le Kang, 2024. "Parental experiences orchestrate locust egg hatching synchrony by regulating nuclear export of precursor miRNA," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. 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.
    3. Karl E. Bauer & Niklas Bargenda & Rico Schieweck & Christin Illig & Inmaculada Segura & Max Harner & Michael A. Kiebler, 2022. "RNA supply drives physiological granule assembly in neurons," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Maritere Uriostegui-Arcos & Steven T. Mick & Zhuo Shi & Rufuto Rahman & Ana Fiszbein, 2023. "Splicing activates transcription from weak promoters upstream of alternative exons," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Toki Kobayashi & Kenta Shimba & Taiyo Narumi & Takahiro Asahina & Kiyoshi Kotani & Yasuhiko Jimbo, 2024. "Revealing single-neuron and network-activity interaction by combining high-density microelectrode array and optogenetics," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Yang Cao & Huachun Liu & Shannon S. Lu & Krysten A. Jones & Anitha P. Govind & Okunola Jeyifous & Christine Q. Simmons & Negar Tabatabaei & William N. Green & Jimmy. L. Holder & Soroush Tahmasebi & Al, 2023. "RNA-based translation activators for targeted gene upregulation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    7. Haoqing Shen & Omer An & Xi Ren & Yangyang Song & Sze Jing Tang & Xin-Yu Ke & Jian Han & Daryl Jin Tai Tay & Vanessa Hui En Ng & Fernando Bellido Molias & Priyankaa Pitcheshwar & Ka Wai Leong & Ker-Ka, 2022. "ADARs act as potent regulators of circular transcriptome in cancer," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Hannah E. Salapa & Patricia A. Thibault & Cole D. Libner & Yulian Ding & Joseph-Patrick W. E. Clarke & Connor Denomy & Catherine Hutchinson & Hashim M. Abidullah & S. Austin Hammond & Landon Pastushok, 2024. "hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    9. Takeshi Kaizuka & Takehiro Suzuki & Noriyuki Kishi & Kota Tamada & Manfred W. Kilimann & Takehiko Ueyama & Masahiko Watanabe & Tomomi Shimogori & Hideyuki Okano & Naoshi Dohmae & Toru Takumi, 2024. "Remodeling of the postsynaptic proteome in male mice and marmosets during synapse development," Nature Communications, Nature, vol. 15(1), pages 1-17, 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:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38273-3. 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: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    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.