A high-throughput screen identifies small molecule modulators of alternative splicing by targeting RNA G-quadruplexes.
Alternative Splicing
/ drug effects
Emetine
/ pharmacology
Exons
/ drug effects
G-Quadruplexes
/ drug effects
High-Throughput Screening Assays
Humans
Nucleic Acid Conformation
/ drug effects
RNA
/ chemistry
RNA Splicing
/ drug effects
RNA Splicing Factors
/ chemistry
Small Molecule Libraries
/ pharmacology
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
23 04 2019
23 04 2019
Historique:
accepted:
16
01
2019
revised:
08
01
2019
received:
22
10
2018
pubmed:
31
1
2019
medline:
11
10
2019
entrez:
31
1
2019
Statut:
ppublish
Résumé
RNA secondary structures have been increasingly recognized to play an important regulatory role in post-transcriptional gene regulation. We recently showed that RNA G-quadruplexes, which serve as cis-elements to recruit splicing factors, play a critical role in regulating alternative splicing during the epithelial-mesenchymal transition. In this study, we performed a high-throughput screen using a dual-color splicing reporter to identify chemical compounds capable of regulating G-quadruplex-dependent alternative splicing. We identify emetine and its analog cephaeline as small molecules that disrupt RNA G-quadruplexes, resulting in inhibition of G-quadruplex-dependent alternative splicing. Transcriptome analysis reveals that emetine globally regulates alternative splicing, including splicing of variable exons that contain splice site-proximal G-quadruplexes. Our data suggest the use of emetine and cephaeline for investigating mechanisms of G-quadruplex-associated alternative splicing.
Identifiants
pubmed: 30698802
pii: 5304186
doi: 10.1093/nar/gkz036
pmc: PMC6468248
doi:
Substances chimiques
RNA Splicing Factors
0
Small Molecule Libraries
0
RNA
63231-63-0
Emetine
X8D5EPO80M
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3667-3679Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM110146
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Nucleic Acids Res. 2012 Jun;40(11):4727-41
pubmed: 22351747
Nat Genet. 2008 Dec;40(12):1413-5
pubmed: 18978789
Nature. 2008 Nov 27;456(7221):470-6
pubmed: 18978772
Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9319-24
pubmed: 18591662
J Biomol Screen. 2013 Feb;18(2):180-90
pubmed: 22972848
Nat Biotechnol. 2001 May;19(5):434-9
pubmed: 11329012
Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54
pubmed: 20713713
Carcinogenesis. 2011 Mar;32(3):271-8
pubmed: 21112961
Sci Rep. 2017 Apr 6;7(1):708
pubmed: 28386116
Nucleic Acids Res. 2012 May;40(9):4137-45
pubmed: 22266651
Neuron. 2014 Sep 3;83(5):1043-50
pubmed: 25132468
J Med Chem. 2017 Dec 14;60(23):9448-9461
pubmed: 29140695
RNA. 2008 Jul;14(7):1290-6
pubmed: 18515550
Cell Rep. 2014 Jun 26;7(6):1900-13
pubmed: 24910439
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11218-23
pubmed: 18678901
Nat Chem Biol. 2017 Jan;13(1):18-20
pubmed: 27820800
FEBS Lett. 2015 Jun 22;589(14):1653-68
pubmed: 25979174
Nature. 2014 Jan 30;505(7485):696-700
pubmed: 24270811
Nat Protoc. 2012 Mar 01;7(3):562-78
pubmed: 22383036
Nat Chem Biol. 2007 Apr;3(4):218-21
pubmed: 17322877
Chem Biol. 2007 Dec;14(12):1386-92
pubmed: 18096507
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8764-9
pubmed: 15939885
Nat Rev Drug Discov. 2011 Apr;10(4):261-75
pubmed: 21455236
Genes Dev. 2014 Jun 1;28(11):1191-203
pubmed: 24840202
Nucleic Acids Res. 2018 Jan 25;46(2):886-896
pubmed: 29156002
Neurobiol Aging. 2012 May;33(5):1012.e11-24
pubmed: 22118946
Mol Biol (Mosk). 2016 Nov-Dec;50(6):935-943
pubmed: 28064309
J Clin Invest. 2011 Mar;121(3):1064-74
pubmed: 21393860
Org Biomol Chem. 2010 Jun 21;8(12):2771-6
pubmed: 20436976
Nucleic Acids Res. 2017 Jan 25;45(2):631-642
pubmed: 28123036
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
J Biol Chem. 2014 Feb 21;289(8):4653-9
pubmed: 24371143
Elife. 2016 Sep 13;5:
pubmed: 27623008
Nucleic Acids Res. 2017 Feb 28;45(4):1584-1595
pubmed: 28013268
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Genome Res. 2013 Jun;23(6):998-1007
pubmed: 23636947
Genes Dev. 2017 Nov 15;31(22):2296-2309
pubmed: 29269483
RNA. 2008 Aug;14(8):1463-9
pubmed: 18579871
RNA Biol. 2010 Jul-Aug;7(4):462-73
pubmed: 20639696
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Genes Dev. 2011 Feb 1;25(3):220-5
pubmed: 21289067
Mol Cell. 2017 Feb 2;65(3):539-553.e7
pubmed: 28157508
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
EMBO Rep. 2011 Jul 01;12(7):697-704
pubmed: 21566646
Nucleic Acids Res. 2006;34(22):e148
pubmed: 17142220
RNA Biol. 2011 Sep-Oct;8(5):802-5
pubmed: 21734463
Nucleic Acids Res. 2013 Jun;41(11):5898-911
pubmed: 23609544
Elife. 2016 Oct 25;5:
pubmed: 27779468
Methods. 2012 May;57(1):64-75
pubmed: 22450044
Wiley Interdiscip Rev RNA. 2013 Sep-Oct;4(5):547-66
pubmed: 23765697
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5593-601
pubmed: 25480548
Nucleic Acids Res. 2006 May 10;34(9):2536-49
pubmed: 16687659
J Am Chem Soc. 2016 Jul 27;138(29):9037-40
pubmed: 27410677