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

Autor:	Ling JP; Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jling@jhu.edu.; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jling@jhu.edu.; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, 21218, USA. jling@jhu.edu., Bygrave AM; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Santiago CP; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Carmen-Orozco RP; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Trinh VT; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Yu M; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA.; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA., Li Y; Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Liu Y; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Bowden KD; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA., Duncan LH; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Han J; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Taneja K; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Dongmo R; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Babola TA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA., Parker P; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Jiang L; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Leavey PJ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Smith JJ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, 21218, USA., Vistein R; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, 21218, USA., Gimmen MY; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Dubner B; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Helmenstine E; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Teodorescu P; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Karantanos T; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Ghiaur G; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Kanold PO; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, 21218, USA.; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA., Bergles D; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, 21218, USA., Langmead B; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, 21218, USA.; Department of Computer Science, Johns Hopkins University, Baltimore, MD, 21218, USA., Sun S; Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Nielsen KJ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, 21218, USA.; Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, 21218, USA., Peachey N; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA.; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA.; Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, 44106, USA., Singh MS; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Dalton WB; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Rajaii F; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Huganir RL; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, 21218, USA., Blackshaw S; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. sblack@jhmi.edu.; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. sblack@jhmi.edu.; Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, 21218, USA. sblack@jhmi.edu.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. sblack@jhmi.edu.; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. sblack@jhmi.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2022 Oct 01; Vol. 13 (1), pp. 5773. Date of Electronic Publication: 2022 Oct 01.
DOI:	10.1038/s41467-022-33523-2
Abstrakt:	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. (© 2022. The Author(s).)
Databáze:	MEDLINE
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