A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function.
Animals
Autoimmunity
/ immunology
CRISPR-Cas Systems
/ genetics
Cell Line, Tumor
Clustered Regularly Interspaced Short Palindromic Repeats
/ genetics
Disease Models, Animal
Forkhead Transcription Factors
/ genetics
Gene Expression Regulation
/ genetics
HEK293 Cells
Humans
Mice, Inbred C57BL
Mice, Knockout
Neoplasms
/ immunology
Nucleosomes
/ immunology
RNA, Guide, Kinetoplastida
/ genetics
T-Lymphocytes, Regulatory
/ cytology
Transcription Factors
/ genetics
Brd9
CRISPR
Foxp3
GBAF
SWI/SNF
Treg
ncBAF
screen
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
14 07 2020
14 07 2020
Historique:
received:
20
02
2020
revised:
20
04
2020
accepted:
12
06
2020
pubmed:
9
7
2020
medline:
24
3
2021
entrez:
9
7
2020
Statut:
ppublish
Résumé
Regulatory T (Treg) cells play a pivotal role in suppressing auto-reactive T cells and maintaining immune homeostasis. Treg cell development and function are dependent on the transcription factor Foxp3. Here, we performed a genome-wide CRISPR loss-of-function screen to identify Foxp3 regulators in mouse primary Treg cells. Foxp3 regulators were enriched in genes encoding subunits of the SWI/SNF nucleosome-remodeling and SAGA chromatin-modifying complexes. Among the three SWI/SNF-related complexes, the Brd9-containing non-canonical (nc) BAF complex promoted Foxp3 expression, whereas the PBAF complex was repressive. Chemical-induced degradation of Brd9 led to reduced Foxp3 expression and reduced Treg cell function in vitro. Brd9 ablation compromised Treg cell function in inflammatory disease and tumor immunity in vivo. Furthermore, Brd9 promoted Foxp3 binding and expression of a subset of Foxp3 target genes. Our findings provide an unbiased analysis of the genetic networks regulating Foxp3 and reveal ncBAF as a target for therapeutic manipulation of Treg cell function.
Identifiants
pubmed: 32640256
pii: S1074-7613(20)30266-1
doi: 10.1016/j.immuni.2020.06.011
pmc: PMC7341821
pii:
doi:
Substances chimiques
Brd9 protein, mouse
0
Forkhead Transcription Factors
0
Foxp3 protein, mouse
0
Nucleosomes
0
RNA, Guide
0
Transcription Factors
0
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
143-157.e8Subventions
Organisme : NIH HHS
ID : S10 OD023689
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI107027
Pays : United States
Organisme : NIGMS NIH HHS
ID : F32 GM128377
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI151123
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009370
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests A patent application has been filed based on the findings described in this study.
Références
Science. 2014 Jan 3;343(6166):84-87
pubmed: 24336571
Eur J Immunol. 2008 Jun;38(6):1654-63
pubmed: 18493985
J Immunol. 2007 Jan 1;178(1):280-90
pubmed: 17182565
Cell. 2014 Aug 14;158(4):734-748
pubmed: 25126782
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Annu Rev Immunol. 2012;30:531-64
pubmed: 22224781
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
EMBO J. 2013 Feb 6;32(3):395-408
pubmed: 23321680
Nat Commun. 2018 Dec 3;9(1):5139
pubmed: 30510198
Nat Immunol. 2009 Nov;10(11):1170-7
pubmed: 19767756
Cell. 2014 Aug 14;158(4):749-763
pubmed: 25126783
Nat Cell Biol. 2018 Dec;20(12):1410-1420
pubmed: 30397315
J Exp Med. 2007 Jul 9;204(7):1543-51
pubmed: 17591856
Immunity. 2008 Jul 18;29(1):44-56
pubmed: 18585065
Nat Biotechnol. 2016 Feb;34(2):184-191
pubmed: 26780180
Immunity. 2013 Aug 22;39(2):259-71
pubmed: 23973222
Cell Res. 2017 Jan;27(1):109-118
pubmed: 27995907
Nature. 2013 Sep 12;501(7466):252-6
pubmed: 23913274
Sci Rep. 2017 Nov 20;7(1):15854
pubmed: 29158538
J Immunol. 2009 Jan 1;182(1):259-73
pubmed: 19109157
Cell. 2018 Dec 13;175(7):1958-1971.e15
pubmed: 30449619
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11903-8
pubmed: 18695219
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5919-24
pubmed: 20231436
Immunity. 2009 Oct 16;31(4):609-20
pubmed: 19800266
Angew Chem Int Ed Engl. 2017 May 15;56(21):5738-5743
pubmed: 28418626
J Immunol. 2009 Jun 1;182(11):6648-52
pubmed: 19454658
Genes Dev. 2015 Jul 1;29(13):1343-55
pubmed: 26159994
Nat Commun. 2018 May 29;9(1):2095
pubmed: 29844370
Nature. 2010 Feb 11;463(7282):808-12
pubmed: 20072126
Nat Immunol. 2007 May;8(5):457-62
pubmed: 17440451
Nat Immunol. 2008 Feb;9(2):194-202
pubmed: 18157133
Cell. 2012 Sep 28;151(1):153-66
pubmed: 23021222
Immunity. 2013 Aug 22;39(2):272-85
pubmed: 23973223
Cell. 2008 May 30;133(5):775-87
pubmed: 18510923
Genome Biol. 2015 Dec 16;16:281
pubmed: 26673418
Nucleic Acids Res. 1991 May 11;19(9):2499
pubmed: 2041787
Genome Biol. 2014;15(12):554
pubmed: 25476604
Nat Immunol. 2017 Feb;18(2):173-183
pubmed: 27992401
Immunity. 2009 Jun 19;30(6):832-44
pubmed: 19538929
Immunity. 2012 Sep 21;37(3):475-86
pubmed: 22921379
Immunity. 2007 Nov;27(5):786-800
pubmed: 18024188
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
J Immunol. 2018 Jul 15;201(2):481-492
pubmed: 29884702
Nat Methods. 2013 Dec;10(12):1213-8
pubmed: 24097267
Immunity. 2010 May 28;32(5):642-53
pubmed: 20471291
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
J Exp Med. 2009 Apr 13;206(4):751-60
pubmed: 19332874
PLoS One. 2014 Jul 22;9(7):e103084
pubmed: 25051498
Cell. 2014 Oct 9;159(2):440-55
pubmed: 25263330
Trends Biochem Sci. 2017 Nov;42(11):850-861
pubmed: 28964624
J Exp Med. 2003 Dec 15;198(12):1875-86
pubmed: 14676299
Nat Commun. 2019 Apr 3;10(1):1523
pubmed: 30944313
Nat Methods. 2017 Oct;14(10):959-962
pubmed: 28846090
Curr Opin Cell Biol. 2010 Jun;22(3):374-82
pubmed: 20363118
Nat Immunol. 2016 Nov;17(11):1322-1333
pubmed: 27595233
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Nat Immunol. 2008 Jun;9(6):632-40
pubmed: 18438410
Immunity. 2009 Dec 18;31(6):921-31
pubmed: 20064449
Trends Immunol. 2014 Aug;35(8):368-78
pubmed: 25047417
Nature. 2020 Jun;582(7812):416-420
pubmed: 32499641