Cell-specific regulation of gene expression using splicing-dependent frameshifting.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 10 2022
01 10 2022
Historique:
received:
14
03
2022
accepted:
21
09
2022
entrez:
1
10
2022
pubmed:
2
10
2022
medline:
5
10
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36182931
doi: 10.1038/s41467-022-33523-2
pii: 10.1038/s41467-022-33523-2
pmc: PMC9526712
doi:
Substances chimiques
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5773Subventions
Organisme : NEI NIH HHS
ID : K08 EY027093
Pays : United States
Organisme : NIMH NIH HHS
ID : RF1 MH123237
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL159306
Pays : United States
Organisme : NINDS NIH HHS
ID : R37 NS036715
Pays : United States
Organisme : NEI NIH HHS
ID : T32 EY007143
Pays : United States
Organisme : NEI NIH HHS
ID : R24 EY027283
Pays : United States
Organisme : NIH HHS
ID : S10 OD026859
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY033103
Pays : United States
Organisme : NIH HHS
ID : T32 OD011089
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Elife. 2016 Mar 24;5:
pubmed: 27011354
Nat Biomed Eng. 2022 Feb;6(2):157-167
pubmed: 35190679
Curr Protoc Mouse Biol. 2018 Mar;8(1):1-16
pubmed: 30040236
N Engl J Med. 2014 Nov 20;371(21):1994-2004
pubmed: 25409372
Gene Ther. 2010 Sep;17(9):1162-74
pubmed: 20428215
PLoS One. 2010 Jun 03;5(6):e10946
pubmed: 20532173
Oncogenesis. 2021 May 3;10(5):36
pubmed: 33941763
PLoS One. 2011;6(4):e18556
pubmed: 21602908
Genome Biol. 2021 Mar 31;22(1):94
pubmed: 33789710
Lancet. 2016 Aug 13;388(10045):661-72
pubmed: 27375040
Neuron. 2015 Jul 1;87(1):14-27
pubmed: 26139367
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6916-21
pubmed: 9192666
Wiley Interdiscip Rev RNA. 2020 Jul;11(4):e1585
pubmed: 31922356
J Clin Oncol. 2015 Sep 1;33(25):2780-8
pubmed: 26014293
Hum Gene Ther. 2012 Oct;23(10):1101-15
pubmed: 22845794
Cell Rep. 2018 Jul 10;24(2):294-303
pubmed: 29996091
Gene Ther. 2010 Apr;17(4):486-93
pubmed: 20010626
Nature. 2019 Oct;574(7778):432-436
pubmed: 31597964
Mol Ther Methods Clin Dev. 2014 Nov 12;1:14053
pubmed: 26052521
Mol Ther. 2018 Oct 3;26(10):2407-2417
pubmed: 30078764
Invest Ophthalmol Vis Sci. 2007 Sep;48(9):3954-61
pubmed: 17724172
Hum Gene Ther. 2013 Dec;24(12):982-92
pubmed: 24067103
J Neurosci. 2020 Jan 29;40(5):958-973
pubmed: 31831521
Nat Rev Drug Discov. 2019 May;18(5):358-378
pubmed: 30710128
Curr Opin Virol. 2016 Dec;21:75-80
pubmed: 27596608
Nat Neurosci. 2019 Oct;22(10):1709-1717
pubmed: 31451803
Science. 1994 Nov 11;266(5187):1059-62
pubmed: 7973663
Genome Biol. 2021 Nov 29;22(1):323
pubmed: 34844637
Nat Genet. 2000 Jul;25(3):306-10
pubmed: 10888879
Neuron. 2012 Nov 8;76(3):503-10
pubmed: 23141062
Prog Retin Eye Res. 2008 Mar;27(2):213-35
pubmed: 18328765
Mol Brain. 2016 May 10;9(1):52
pubmed: 27164903
FASEB J. 2010 Apr;24(4):1178-91
pubmed: 19952284
Nat Rev Genet. 2020 Apr;21(4):255-272
pubmed: 32042148
Front Mol Neurosci. 2012 Apr 11;5:34
pubmed: 22514516
Nat Biotechnol. 2022 Jul;40(7):1103-1113
pubmed: 35241838
Int J Mol Sci. 2020 Jun 12;21(12):
pubmed: 32545533
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
Nat Biotechnol. 2021 Dec;39(12):1517-1520
pubmed: 34211161
J Neurosci. 2000 Mar 15;20(6):2166-74
pubmed: 10704491
Science. 2016 Jan 22;351(6271):407-411
pubmed: 26721686
iScience. 2020 Mar 27;23(3):100888
pubmed: 32087575
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Cell Rep. 2021 Mar 30;34(13):108754
pubmed: 33789096
Methods Mol Biol. 2018;1715:101-111
pubmed: 29188509
Cell. 2019 Jan 24;176(3):535-548.e24
pubmed: 30661751
Blood. 2005 Jun 1;105(11):4247-54
pubmed: 15728125
Nat Commun. 2018 Dec 7;9(1):5227
pubmed: 30531949
J Virol. 2001 Apr;75(7):3314-24
pubmed: 11238857
Nat Commun. 2019 Jun 17;10(1):2673
pubmed: 31209208
Prog Retin Eye Res. 2016 May;52:47-63
pubmed: 26773759
Gene Ther. 2003 Feb;10(4):337-47
pubmed: 12595892
J Neurosci. 1997 Nov 1;17(21):8118-28
pubmed: 9334387
Nat Biotechnol. 2005 Nov;23(11):1418-23
pubmed: 16244656
Nat Neurosci. 2016 Dec;19(12):1743-1749
pubmed: 27798629
Invest Ophthalmol Vis Sci. 1991 Dec;32(13):3198-208
pubmed: 1748551
Hum Mutat. 2001;17(1):42-51
pubmed: 11139241
Pigment Cell Melanoma Res. 2012 Mar;25(2):182-7
pubmed: 22236444
Genome Res. 2013 Jun;23(6):998-1007
pubmed: 23636947
Curr Opin Neurobiol. 2020 Aug;63:67-76
pubmed: 32344323
Molecules. 2018 Jun 21;23(7):
pubmed: 29933586
PLoS Genet. 2013;9(2):e1003337
pubmed: 23468662
Nature. 2021 Aug;596(7871):291-295
pubmed: 34321659
Mol Ther Oncolytics. 2021 May 05;21:340-355
pubmed: 34141871
J Clin Invest. 2019 Aug 8;129(11):4708-4723
pubmed: 31393856
Mol Cell Neurosci. 2004 Jan;25(1):103-10
pubmed: 14962744
Science. 1990 Sep 28;249(4976):1580-5
pubmed: 1699275
Nat Rev Neurosci. 2021 Mar;22(3):137-151
pubmed: 33420412
Hum Mol Genet. 2001 Oct 1;10(21):2353-61
pubmed: 11689482
J Comp Neurol. 1984 Mar 20;224(1):71-84
pubmed: 6715580
Nat Biotechnol. 2020 Jun;38(6):708-714
pubmed: 32518404
Nat Genet. 2013 Oct;45(10):1113-20
pubmed: 24071849
J Neurosci Methods. 2010 Jan 30;186(1):60-7
pubmed: 19903493
Int J Cancer. 1995 Jul 17;62(2):155-61
pubmed: 7622289
Nucleic Acids Res. 2006;34(22):e148
pubmed: 17142220
Nat Methods. 2019 Jul;16(7):649-657
pubmed: 31209382
Nat Commun. 2020 Jan 9;11(1):137
pubmed: 31919425
Nature. 2018 Nov;563(7729):72-78
pubmed: 30382198
J Neurosci. 1997 Jan 1;17(1):58-69
pubmed: 8987736
In Silico Biol. 2004;4(4):387-93
pubmed: 15217358
Nat Methods. 2014 Feb;11(2):121-2
pubmed: 24481215
Nucleic Acid Ther. 2018 Oct;28(5):285-296
pubmed: 30088967
Trans Am Ophthalmol Soc. 2016 Aug;114:T5
pubmed: 28018010
Nat Med. 2018 Sep;24(9):1317-1323
pubmed: 30013199
Nat Commun. 2018 Apr 10;9(1):1366
pubmed: 29636450
Bioinformatics. 2018 Jan 1;34(1):114-116
pubmed: 28968689
Annu Rev Neurosci. 2018 Jul 8;41:323-348
pubmed: 29709207
FEBS J. 2010 Feb;277(4):856-66
pubmed: 20082635
J Gene Med. 2003 Sep;5(9):757-64
pubmed: 12950066