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

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 Taneja, Rochinelle Dongmo, Travis A. Babola, Patrick Parker, Lizhi Jiang, Patrick J. Leavey, Jennifer J. Smith, Rachel Vistein, Megan Y. Gimmen, Benjamin Dubner, Eric Helmenstine, Patric Teodorescu, Theodoros Karantanos, Gabriel Ghiaur, Patrick O. Kanold, Dwight Bergles, Ben Langmead, Shuying Sun, Kristina J. Nielsen, Neal Peachey, Mandeep S. Singh, W. Brian Dalton, Fatemeh Rajaii, Richard L. Huganir and Seth Blackshaw ()
Additional contact information
Jonathan P. Ling: Johns Hopkins University School of Medicine
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
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
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
Rachel Vistein: Johns Hopkins University School of Medicine
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
Dwight Bergles: Johns Hopkins University School of Medicine
Ben Langmead: Johns Hopkins University
Shuying Sun: Johns Hopkins University School of Medicine
Kristina J. Nielsen: Johns Hopkins University School of Medicine
Neal Peachey: Cleveland Clinic Foundation
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
Seth Blackshaw: Johns Hopkins University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33523-2

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