A deep learning approach to identify gene targets of a therapeutic for human splicing disorders.
Animals
Computational Biology
Cystic Fibrosis Transmembrane Conductance Regulator
/ genetics
Deep Learning
Exons
Gene Targeting
/ methods
HEK293 Cells
Humans
Mice
Mice, Transgenic
MutL Protein Homolog 1
/ genetics
Mutation
Phenethylamines
/ administration & dosage
Pyridazines
/ administration & dosage
RNA Splicing
Sterol Esterase
/ genetics
Transcriptome
tau Proteins
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 06 2021
07 06 2021
Historique:
received:
28
02
2020
accepted:
07
05
2021
entrez:
8
6
2021
pubmed:
9
6
2021
medline:
23
6
2021
Statut:
epublish
Résumé
Pre-mRNA splicing is a key controller of human gene expression. Disturbances in splicing due to mutation lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of splicing modulator compounds (SMCs) have been recently identified and establish that pre-mRNA splicing represents a target for therapy. We describe herein the identification of BPN-15477, a SMC that restores correct splicing of ELP1 exon 20. Using transcriptome sequencing from treated fibroblast cells and a machine learning approach, we identify BPN-15477 responsive sequence signatures. We then leverage this model to discover 155 human disease genes harboring ClinVar mutations predicted to alter pre-mRNA splicing as targets for BPN-15477. Splicing assays confirm successful correction of splicing defects caused by mutations in CFTR, LIPA, MLH1 and MAPT. Subsequent validations in two disease-relevant cellular models demonstrate that BPN-15477 increases functional protein, confirming the clinical potential of our predictions.
Identifiants
pubmed: 34099697
doi: 10.1038/s41467-021-23663-2
pii: 10.1038/s41467-021-23663-2
pmc: PMC8185002
doi:
Substances chimiques
CFTR protein, human
0
MAPT protein, human
0
MLH1 protein, human
0
Phenethylamines
0
Pyridazines
0
tau Proteins
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
LIPA protein, human
EC 3.1.1.13
Sterol Esterase
EC 3.1.1.13
MutL Protein Homolog 1
EC 3.6.1.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3332Subventions
Organisme : NINDS NIH HHS
ID : R01 NS102423
Pays : United States
Organisme : NINDS NIH HHS
ID : R37 NS095640
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS095437
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS078025
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK044003
Pays : United States
Références
J Biol Chem. 2011 Sep 2;286(35):30624-30635
pubmed: 21757691
Cell. 2009 Feb 20;136(4):777-93
pubmed: 19239895
RNA. 2018 Sep;24(9):1119-1132
pubmed: 29941426
J Pediatr Gastroenterol Nutr. 2013 Jun;56(6):682-5
pubmed: 23403440
Mol Genet Metab. 2012 Feb;105(2):244-8
pubmed: 22138108
Int J Biochem Cell Biol. 2007;39(7-8):1432-49
pubmed: 17416541
J Cyst Fibros. 2016 May;15(3):285-94
pubmed: 26694805
RNA. 2007 Oct;13(10):1609-24
pubmed: 17684229
Methods Mol Biol. 2011;741:155-69
pubmed: 21594784
N Engl J Med. 2018 Oct 25;379(17):1612-1620
pubmed: 30334692
N Engl J Med. 2015 Jul 16;373(3):220-31
pubmed: 25981758
Eur J Hum Genet. 2014 Jun;22(6):784-91
pubmed: 24129438
Hum Genet. 2001 Dec;109(6):592-601
pubmed: 11810271
Wiley Interdiscip Rev RNA. 2013 May-Jun;4(3):247-66
pubmed: 23512601
Hepatology. 2013 Sep;58(3):958-65
pubmed: 23424026
J Mol Endocrinol. 2017 Aug;59(2):R93-R107
pubmed: 28716821
Mol Cell Biol. 1996 Jul;16(7):3317-26
pubmed: 8668147
J Comput Biol. 2004;11(2-3):377-94
pubmed: 15285897
Am J Hum Genet. 2019 Apr 4;104(4):638-650
pubmed: 30905397
Bioinformatics. 2019 Dec 15;35(24):5235-5242
pubmed: 31077303
BMC Med Genet. 2007 Feb 12;8:4
pubmed: 17295913
Hum Mol Genet. 2004 Feb 15;13(4):429-36
pubmed: 14709595
Am J Hum Genet. 2017 May 4;100(5):751-765
pubmed: 28475858
Hum Mutat. 2009 Dec;30(12):1657-66
pubmed: 19937601
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
BMC Mol Biol. 2015 Sep 24;16:16
pubmed: 26400733
Genomics. 2007 Sep;90(3):389-96
pubmed: 17644305
Nat Genet. 2013 Oct;45(10):1160-7
pubmed: 23974870
Nat Genet. 2002 Dec;32(4):650-4
pubmed: 12426569
PLoS One. 2013;8(3):e59916
pubmed: 23536893
Hum Mol Genet. 1999 Jul;8(7):1177-83
pubmed: 10369862
Hum Mutat. 2006 Nov;27(11):1104-14
pubmed: 16937374
Nat Med. 2019 Jun;25(6):911-919
pubmed: 31160820
Clin Chem Lab Med. 2015 Oct;53(11):1719-23
pubmed: 25781545
Am J Hum Genet. 2003 Mar;72(3):749-58
pubmed: 12577200
N Engl J Med. 2017 Nov 23;377(21):2013-2023
pubmed: 29099344
Bioinformatics. 2011 Jun 15;27(12):1653-9
pubmed: 21543442
Eur J Endocrinol. 2016 May;174(5):R225-38
pubmed: 26628584
Neuropathol Appl Neurobiol. 2005 Aug;31(4):362-73
pubmed: 16008820
Atherosclerosis. 2014 Jul;235(1):21-30
pubmed: 24792990
Fam Cancer. 2012 Sep;11(3):441-7
pubmed: 22714864
Nature. 2008 Nov 27;456(7221):470-6
pubmed: 18978772
Cell. 2019 Jan 24;176(3):535-548.e24
pubmed: 30661751
N Engl J Med. 2011 Nov 3;365(18):1663-72
pubmed: 22047557
Nature. 2020 May;581(7809):444-451
pubmed: 32461652
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7737-41
pubmed: 9636220
J Med Chem. 2018 Aug 09;61(15):6501-6517
pubmed: 30044619
Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2764-9
pubmed: 25675486
J Mol Med (Berl). 2007 Feb;85(2):149-61
pubmed: 17206408
N Engl J Med. 2018 Oct 25;379(17):1599-1611
pubmed: 30334693
Brain Res Mol Brain Res. 2005 Jun 13;137(1-2):104-9
pubmed: 15950767
Neuron. 2015 Sep 23;87(6):1215-1233
pubmed: 26402605
J Cell Sci. 2006 Jul 1;119(Pt 13):2635-41
pubmed: 16787944
Hum Mutat. 2014 Oct;35(10):1249-59
pubmed: 25066652
Sci Transl Med. 2011 Mar 2;3(72):72ra18
pubmed: 21368223
PLoS Genet. 2018 Mar 5;14(3):e1007231
pubmed: 29505604
Pediatr Res. 2009 Mar;65(3):341-6
pubmed: 19033881
J Med Chem. 2016 Jul 14;59(13):6070-85
pubmed: 27299569
Biochim Biophys Acta. 2009 Sep-Oct;1789(9-10):624-33
pubmed: 19733268
J Med Chem. 2018 Dec 27;61(24):11021-11036
pubmed: 30407821
Science. 1998 Dec 4;282(5395):1914-7
pubmed: 9836646
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Science. 2014 Aug 8;345(6197):624-5
pubmed: 25104373
Nat Chem Biol. 2015 Jul;11(7):511-7
pubmed: 26030728
Neurol Clin. 2014 Aug;32(3):705-19, viii
pubmed: 25037086
Neurology. 2016 Mar 8;86(10):890-7
pubmed: 26865511
Genome Res. 2011 Sep;21(9):1543-51
pubmed: 21816910
Nature. 1998 Jun 18;393(6686):702-5
pubmed: 9641683
Nucleic Acids Res. 2018 Jun 1;46(10):4833-4844
pubmed: 29672717
RNA. 2018 Dec;24(12):1647-1658
pubmed: 30224349
Hum Mutat. 2007 Jan;28(1):41-53
pubmed: 16964593
Science. 1999 Oct 15;286(5439):531-7
pubmed: 10521349
Science. 2014 Aug 8;345(6197):688-93
pubmed: 25104390
Genes Dev. 2010 Aug 1;24(15):1634-44
pubmed: 20624852
PLoS Genet. 2018 Nov 16;14(11):e1007723
pubmed: 30444886
Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5
pubmed: 24234437
Nat Med. 2019 Jan;25(1):24-29
pubmed: 30617335
Pediatr Res. 2011 Nov;70(5):480-3
pubmed: 21775922
Am J Med Genet A. 2012 Jul;158A(7):1523-5
pubmed: 22628075
Am J Hum Genet. 2018 Jun 7;102(6):1062-1077
pubmed: 29805046
Genomics. 1996 Apr 1;33(1):85-93
pubmed: 8617513
Genome Res. 2016 Jul;26(7):990-9
pubmed: 27197224
Am J Respir Crit Care Med. 2019 May 1;199(9):1116-1126
pubmed: 30888834
SLAS Discov. 2019 Jan;24(1):57-67
pubmed: 30085848
J Mol Diagn. 2006 Feb;8(1):137-40
pubmed: 16436646
Am J Hum Genet. 2015 Jan 8;96(1):93-103
pubmed: 25557785
Hum Biol. 2001 Jun;73(3):403-9
pubmed: 11459421