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Cell-specific regulation of gene expression using splicing-dependent frameshifting

Author

Listed:
  • Jonathan P. Ling

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University)

  • Alexei M. Bygrave

    (Johns Hopkins University School of Medicine)

  • Clayton P. Santiago

    (Johns Hopkins University School of Medicine)

  • Rogger P. Carmen-Orozco

    (Johns Hopkins University School of Medicine)

  • Vickie T. Trinh

    (Johns Hopkins University School of Medicine)

  • Minzhong Yu

    (Cleveland Clinic Foundation
    Cleveland Clinic Lerner College of Medicine of Case Western Reserve University)

  • Yini Li

    (Johns Hopkins University School of Medicine)

  • Ying Liu

    (Johns Hopkins University School of Medicine)

  • Kyra D. Bowden

    (Johns Hopkins University)

  • Leighton H. Duncan

    (Johns Hopkins University School of Medicine)

  • Jeong Han

    (Johns Hopkins University School of Medicine)

  • Kamil Taneja

    (Johns Hopkins University School of Medicine)

  • Rochinelle Dongmo

    (Johns Hopkins University School of Medicine)

  • Travis A. Babola

    (Johns Hopkins University School of Medicine
    Johns Hopkins University)

  • Patrick Parker

    (Johns Hopkins University School of Medicine)

  • Lizhi Jiang

    (Johns Hopkins University School of Medicine)

  • Patrick J. Leavey

    (Johns Hopkins University School of Medicine)

  • Jennifer J. Smith

    (Johns Hopkins University School of Medicine
    Johns Hopkins University)

  • Rachel Vistein

    (Johns Hopkins University School of Medicine
    Johns Hopkins University)

  • Megan Y. Gimmen

    (Johns Hopkins University School of Medicine)

  • Benjamin Dubner

    (Johns Hopkins University School of Medicine)

  • Eric Helmenstine

    (Johns Hopkins University School of Medicine)

  • Patric Teodorescu

    (Johns Hopkins University School of Medicine)

  • Theodoros Karantanos

    (Johns Hopkins University School of Medicine)

  • Gabriel Ghiaur

    (Johns Hopkins University School of Medicine)

  • Patrick O. Kanold

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University)

  • Dwight Bergles

    (Johns Hopkins University School of Medicine
    Johns Hopkins University)

  • Ben Langmead

    (Johns Hopkins University
    Johns Hopkins University)

  • Shuying Sun

    (Johns Hopkins University School of Medicine)

  • Kristina J. Nielsen

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University)

  • Neal Peachey

    (Cleveland Clinic Foundation
    Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
    Research Service, Louis Stokes Cleveland VA Medical Center)

  • Mandeep S. Singh

    (Johns Hopkins University School of Medicine)

  • W. Brian Dalton

    (Johns Hopkins University School of Medicine)

  • Fatemeh Rajaii

    (Johns Hopkins University School of Medicine)

  • Richard L. Huganir

    (Johns Hopkins University School of Medicine
    Johns Hopkins University)

  • Seth Blackshaw

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University School of Medicine)

Abstract

Precise and reliable cell-specific gene delivery remains technically challenging. Here we report a splicing-based approach for controlling gene expression whereby separate translational reading frames are coupled to the inclusion or exclusion of mutated, frameshifting cell-specific alternative exons. Candidate exons are identified by analyzing thousands of publicly available RNA sequencing datasets and filtering by cell specificity, conservation, and local intron length. This method, which we denote splicing-linked expression design (SLED), can be combined in a Boolean manner with existing techniques such as minipromoters and viral capsids. SLED can use strong constitutive promoters, without sacrificing precision, by decoupling the tradeoff between promoter strength and selectivity. AAV-packaged SLED vectors can selectively deliver fluorescent reporters and calcium indicators to various neuronal subtypes in vivo. We also demonstrate gene therapy utility by creating SLED vectors that can target PRPH2 and SF3B1 mutations. The flexibility of SLED technology enables creative avenues for basic and translational research.

Suggested Citation

  • Jonathan P. Ling & Alexei M. Bygrave & Clayton P. Santiago & Rogger P. Carmen-Orozco & Vickie T. Trinh & Minzhong Yu & Yini Li & Ying Liu & Kyra D. Bowden & Leighton H. Duncan & Jeong Han & Kamil Tane, 2022. "Cell-specific regulation of gene expression using splicing-dependent frameshifting," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33523-2
    DOI: 10.1038/s41467-022-33523-2
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    References listed on IDEAS

    as
    1. Alexander Lachmann & Denis Torre & Alexandra B. Keenan & Kathleen M. Jagodnik & Hoyjin J. Lee & Lily Wang & Moshe C. Silverstein & Avi Ma’ayan, 2018. "Massive mining of publicly available RNA-seq data from human and mouse," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    2. Bosiljka Tasic & Zizhen Yao & Lucas T. Graybuck & Kimberly A. Smith & Thuc Nghi Nguyen & Darren Bertagnolli & Jeff Goldy & Emma Garren & Michael N. Economo & Sarada Viswanathan & Osnat Penn & Trygve B, 2018. "Shared and distinct transcriptomic cell types across neocortical areas," Nature, Nature, vol. 563(7729), pages 72-78, November.
    3. Alex Mas Monteys & Amiel A. Hundley & Paul T. Ranum & Luis Tecedor & Amy Muehlmatt & Euyn Lim & Dmitriy Lukashev & Rajeev Sivasankaran & Beverly L. Davidson, 2021. "Regulated control of gene therapies by drug-induced splicing," Nature, Nature, vol. 596(7871), pages 291-295, August.
    4. Melina Mathur & Cameron M. Kim & Sarah A. Munro & Shireen S. Rudina & Eric M. Sawyer & Christina D. Smolke, 2019. "Programmable mutually exclusive alternative splicing for generating RNA and protein diversity," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    5. Daichi Inoue & Guo-Liang Chew & Bo Liu & Brittany C. Michel & Joseph Pangallo & Andrew R. D’Avino & Tyler Hitchman & Khrystyna North & Stanley Chun-Wei Lee & Lillian Bitner & Ariele Block & Amanda R. , 2019. "Spliceosomal disruption of the non-canonical BAF complex in cancer," Nature, Nature, vol. 574(7778), pages 432-436, October.
    Full references (including those not matched with items on IDEAS)

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