Transcription factor protein interactomes reveal genetic determinants in heart disease.
GATA4
GLYR1
NPAC
TBX5
congenital heart disease
de novo variants
disease variants
genetics
protein interactome networks
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
03 03 2022
03 03 2022
Historique:
received:
25
11
2020
revised:
20
08
2021
accepted:
25
01
2022
pubmed:
20
2
2022
medline:
26
4
2022
entrez:
19
2
2022
Statut:
ppublish
Résumé
Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.
Identifiants
pubmed: 35182466
pii: S0092-8674(22)00079-4
doi: 10.1016/j.cell.2022.01.021
pmc: PMC8923057
mid: NIHMS1781265
pii:
doi:
Substances chimiques
GATA4 Transcription Factor
0
Gata4 protein, mouse
0
Nuclear Proteins
0
T-Box Domain Proteins
0
Transcription Factors
0
Glyr1 protein, mouse
EC 1.-
Oxidoreductases
EC 1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
794-814.e30Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL089707
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL146366
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127240
Pays : United States
Organisme : NHLBI NIH HHS
ID : UM1 HL098179
Pays : United States
Organisme : NIEHS NIH HHS
ID : U01 ES032673
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL057181
Pays : United States
Organisme : NHLBI NIH HHS
ID : UM1 HL098166
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD007470
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL098147
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH115747
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL157700
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL131003
Pays : United States
Organisme : NHLBI NIH HHS
ID : R03 HL150412
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests D.S. is scientific co-founder, shareholder, and director of Tenaya Therapeutics. B.G.B. and B.R.C. are scientific co-founders and shareholders of Tenaya Therapeutics. K.S.P. is a shareholder of Tenaya Therapeutics. N.J.K. has received research support from Vir Biotechnology and F. Hoffmann-La Roche. N.J.K. has consulting agreements with the Icahn School of Medicine at Mount Sinai, New York, Maze Therapeutics, and Interline Therapeutics; is a shareholder of Tenaya Therapeutics, Maze Therapeutics, and Interline Therapeutics; and is financially compensated by GEn1E Lifesciences, Inc. and Twist Bioscience Corp.
Références
Cell. 2001 Sep 21;106(6):709-21
pubmed: 11572777
Mol Cell Biol. 2011 Jul;31(13):2641-52
pubmed: 21555454
Genome Med. 2020 Jan 15;12(1):9
pubmed: 31941532
Am J Hum Genet. 2012 Aug 10;91(2):358-64
pubmed: 22795537
Development. 1997 Oct;124(19):3755-64
pubmed: 9367431
Genomics Proteomics Bioinformatics. 2021 Mar 3;:
pubmed: 33676077
Dev Biol. 2006 Sep 15;297(2):566-86
pubmed: 16870172
J Clin Invest. 2017 Sep 1;127(9):3527-3542
pubmed: 28758902
Nat Commun. 2016 Jan 22;7:10477
pubmed: 26795633
Bioinformatics. 2012 Aug 15;28(16):2184-5
pubmed: 22743226
Genet Med. 2015 Jul;17(7):578-86
pubmed: 25356970
PLoS Genet. 2010 Oct 14;6(10):e1001154
pubmed: 20976243
Cell Stem Cell. 2013 Jan 3;12(1):127-37
pubmed: 23168164
Nat Genet. 2015 Jun;47(6):569-76
pubmed: 25915600
Science. 2015 Jan 23;347(6220):1260419
pubmed: 25613900
Circulation. 2020 Dec 15;142(24):2338-2355
pubmed: 33094644
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Genome Med. 2020 Aug 28;12(1):76
pubmed: 32859249
BMC Cardiovasc Disord. 2020 Jan 20;20(1):27
pubmed: 31959127
Nature. 2015 May 28;521(7553):520-4
pubmed: 25807483
JCI Insight. 2017 Mar 23;2(6):e88271
pubmed: 28352650
Eur J Hum Genet. 2018 Jan;26(1):107-116
pubmed: 29203834
Nat Genet. 2020 Aug;52(8):769-777
pubmed: 32601476
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
Sci Rep. 2020 Apr 27;10(1):7046
pubmed: 32341405
Eur J Hum Genet. 2017 Nov;25(11):1268-1272
pubmed: 28832562
Nat Rev Genet. 2017 Oct;18(10):599-612
pubmed: 28804138
Am J Med Genet A. 2017 May;173(5):1383-1389
pubmed: 28371265
Nat Genet. 2006 Jan;38(1):112-7
pubmed: 16311594
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2919-24
pubmed: 10077612
J Comput Aided Mol Des. 2013 Mar;27(3):221-34
pubmed: 23579614
Nat Genet. 2014 Sep;46(9):944-50
pubmed: 25086666
Nat Genet. 2019 May;51(5):772-776
pubmed: 30962618
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12573-8
pubmed: 15310850
Nat Genet. 1997 Jan;15(1):21-9
pubmed: 8988164
J Med Genet. 2007 Dec;44(12):779-83
pubmed: 18055909
Science. 2019 May 31;364(6443):865-870
pubmed: 31147515
Cell. 2016 Feb 25;164(5):999-1014
pubmed: 26875865
Biostatistics. 2008 Apr;9(2):321-32
pubmed: 17728317
Nature. 2003 Jul 24;424(6947):443-7
pubmed: 12845333
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Methods Mol Biol. 2016;1418:391-416
pubmed: 27008025
PLoS Comput Biol. 2012;8(8):e1002638
pubmed: 22912568
BMC Dev Biol. 2013 Mar 25;13:9
pubmed: 23521771
Genes Dev. 1997 Apr 15;11(8):1048-60
pubmed: 9136932
Nat Methods. 2014 Mar;11(3):291-3
pubmed: 24509632
Nat Methods. 2019 Dec;16(12):1289-1296
pubmed: 31740819
Dev Biol. 1999 Jul 1;211(1):100-8
pubmed: 10373308
Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6727-6732
pubmed: 29891665
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
Nat Genet. 2016 Sep;48(9):1060-5
pubmed: 27479907
Nat Commun. 2011 Feb 08;2:187
pubmed: 21304516
Circulation. 2018 Nov 20;138(21):e653-e711
pubmed: 30571578
Nat Genet. 2017 Nov;49(11):1593-1601
pubmed: 28991257
PLoS Comput Biol. 2014 Jun 12;10(6):e1003632
pubmed: 24921629
Dev Biol. 2009 Feb 15;326(2):368-77
pubmed: 19084512
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Nat Commun. 2019 Oct 28;10(1):4907
pubmed: 31659164
Cold Spring Harb Mol Case Stud. 2019 Jun 3;5(3):
pubmed: 31160358
Cell Rep. 2015 Oct 6;13(1):183-195
pubmed: 26411676
PLoS Comput Biol. 2012;8(9):e1002690
pubmed: 23028288
Genes Dev. 2018 May 1;32(9-10):682-694
pubmed: 29759984
Hum Mol Genet. 2014 Feb 15;23(4):980-91
pubmed: 24105469
J Cell Mol Med. 2011 Sep;15(9):1865-77
pubmed: 20874724
Genes Dev. 1997 Apr 15;11(8):1061-72
pubmed: 9136933
BMC Bioinformatics. 2008 Sep 30;9:405
pubmed: 18823568
Cell. 2016 Dec 15;167(7):1734-1749.e22
pubmed: 27984724
Nature. 2017 Oct 11;550(7675):204-213
pubmed: 29022597
Nucleic Acids Res. 2013 Jan;41(Database issue):D991-5
pubmed: 23193258
Genome Biol. 2010;11(3):R25
pubmed: 20196867
Stem Cell Reports. 2015 Apr 14;4(4):621-31
pubmed: 25801505
Dev Cell. 2021 Feb 8;56(3):292-309.e9
pubmed: 33321106
Bioinformatics. 2015 May 1;31(9):1375-81
pubmed: 25535243
Genet Med. 2019 Mar;21(3):572-579
pubmed: 29907796
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
J Biol Chem. 2012 Jul 13;287(29):24255-62
pubmed: 22621927
Bioinformatics. 2007 Nov 1;23(21):2881-7
pubmed: 17881408
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13933-8
pubmed: 19666519
PLoS Comput Biol. 2012;8(7):e1002613
pubmed: 22844240
Proteomics. 2016 Aug;16(15-16):2238-45
pubmed: 27119218
PLoS Genet. 2016 Apr 08;12(4):e1005963
pubmed: 27058611
Hum Mol Genet. 2014 Apr 15;23(8):2145-56
pubmed: 24293546
Nature. 2021 Jul;595(7867):438-443
pubmed: 34163071
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Nat Protoc. 2013 Jan;8(1):162-75
pubmed: 23257984
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Nature. 2013 Jun 13;498(7453):220-3
pubmed: 23665959
Nature. 2015 Mar 12;519(7542):223-8
pubmed: 25533962
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11189-94
pubmed: 16847256
Bioinformatics. 2005 Aug 15;21(16):3448-9
pubmed: 15972284
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Development. 2016 Aug 15;143(16):2882-97
pubmed: 27531948
Nat Rev Genet. 2020 Mar;21(3):137-150
pubmed: 31913361
Bioinformatics. 2017 Aug 01;33(15):2381-2383
pubmed: 28369316
J Cell Sci. 2006 Jan 1;119(Pt 1):115-23
pubmed: 16352664
Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4006-11
pubmed: 21330551
J Clin Invest. 2006 Apr;116(4):929-39
pubmed: 16557299
Am J Hum Genet. 2008 Apr;82(4):949-58
pubmed: 18371930
Pediatr Res. 2010 Oct;68(4):281-5
pubmed: 20581743
Cell Rep. 2019 Dec 10;29(11):3751-3765.e5
pubmed: 31825849
Mol Cell. 2013 Feb 7;49(3):558-70
pubmed: 23260659
Science. 2020 Nov 13;370(6518):
pubmed: 33184181
Elife. 2020 Oct 02;9:
pubmed: 33006316
Circ Res. 2017 Mar 17;120(6):923-940
pubmed: 28302740
Nat Genet. 1997 Jan;15(1):30-5
pubmed: 8988165
Genome Biol. 2015 Dec 10;16:278
pubmed: 26653891
J Hum Genet. 2013 Jul;58(7):439-45
pubmed: 23739122
J Am Heart Assoc. 2014 Nov 25;3(6):e001493
pubmed: 25424575
Nat Med. 2016 May;22(5):547-56
pubmed: 27089514
Protein Sci. 2021 Jan;30(1):187-200
pubmed: 33070389
Nat Genet. 2020 May;52(5):482-493
pubmed: 32341526
Proc Natl Acad Sci U S A. 2007 May 22;104(21):8685-90
pubmed: 17502601
J Biol Chem. 1991 Apr 25;266(12):7759-68
pubmed: 1850419
J Chem Inf Model. 2019 Sep 23;59(9):3927-3937
pubmed: 31408337
Development. 1998 Mar;125(5):813-24
pubmed: 9449664
Cell. 2018 Feb 8;172(4):650-665
pubmed: 29425488
Dev Cell. 2016 Feb 8;36(3):262-75
pubmed: 26859351
Biol Psychiatry. 2019 Feb 15;85(4):287-297
pubmed: 29724491
J Mol Cell Cardiol. 2007 Dec;43(6):677-85
pubmed: 17643447
Biochimie. 2014 Sep;104:61-9
pubmed: 24878278
Am J Hum Genet. 2010 Jun 11;86(6):839-49
pubmed: 20493459
Science. 2015 Dec 4;350(6265):1262-6
pubmed: 26785492
Bioinformatics. 2015 Aug 1;31(15):2595-7
pubmed: 25810428
Sci Rep. 2018 Oct 18;8(1):15369
pubmed: 30337622
Cell Rep. 2019 Apr 9;27(2):387-399.e7
pubmed: 30970244
Nature. 2019 Aug;572(7767):120-124
pubmed: 31341279