Systematic identification of genomic elements that regulate FCGR2A expression and harbor variants linked with autoimmune disease.

Autoimmune Diseases / genetics Binding Sites Enhancer Elements, Genetic Genomics Genotype Humans Receptors, IgG / genetics

Journal

Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958

Informations de publication

Date de publication:
22 06 2022
Historique:
received: 27 10 2021
revised: 20 12 2021
accepted: 23 12 2021
pubmed: 1 1 2022
medline: 1 7 2022
entrez: 31 12 2021
Statut: ppublish

Résumé

FCGR2A binds antibody-antigen complexes to regulate the abundance of circulating and deposited complexes along with downstream immune and autoimmune responses. Although the abundance of FCRG2A may be critical in immune-mediated diseases, little is known about whether its surface expression is regulated through cis genomic elements and non-coding variants. In the current study, we aimed to characterize the regulation of FCGR2A expression, the impact of genetic variation and its association with autoimmune disease. We applied CRISPR-based interference and editing to scrutinize 1.7 Mb of open chromatin surrounding the FCGR2A gene to identify regulatory elements. Relevant transcription factors (TFs) binding to these regions were defined through public databases. Genetic variants affecting regulation were identified using luciferase reporter assays and were verified in a cohort of 1996 genotyped healthy individuals using flow cytometry. We identified a complex proximal region and five distal enhancers regulating FCGR2A. The proximal region split into subregions upstream and downstream of the transcription start site, was enriched in binding of inflammation-regulated TFs, and harbored a variant associated with FCGR2A expression in primary myeloid cells. One distal enhancer region was occupied by CCCTC-binding factor (CTCF) whose binding site was disrupted by a rare genetic variant, altering gene expression. The FCGR2A gene is regulated by multiple proximal and distal genomic regions, with links to autoimmune disease. These findings may open up novel therapeutic avenues where fine-tuning of FCGR2A levels may constitute a part of treatment strategies for immune-mediated diseases.

Sections du résumé

BACKGROUND
FCGR2A binds antibody-antigen complexes to regulate the abundance of circulating and deposited complexes along with downstream immune and autoimmune responses. Although the abundance of FCRG2A may be critical in immune-mediated diseases, little is known about whether its surface expression is regulated through cis genomic elements and non-coding variants. In the current study, we aimed to characterize the regulation of FCGR2A expression, the impact of genetic variation and its association with autoimmune disease.
METHODS
We applied CRISPR-based interference and editing to scrutinize 1.7 Mb of open chromatin surrounding the FCGR2A gene to identify regulatory elements. Relevant transcription factors (TFs) binding to these regions were defined through public databases. Genetic variants affecting regulation were identified using luciferase reporter assays and were verified in a cohort of 1996 genotyped healthy individuals using flow cytometry.
RESULTS
We identified a complex proximal region and five distal enhancers regulating FCGR2A. The proximal region split into subregions upstream and downstream of the transcription start site, was enriched in binding of inflammation-regulated TFs, and harbored a variant associated with FCGR2A expression in primary myeloid cells. One distal enhancer region was occupied by CCCTC-binding factor (CTCF) whose binding site was disrupted by a rare genetic variant, altering gene expression.
CONCLUSIONS
The FCGR2A gene is regulated by multiple proximal and distal genomic regions, with links to autoimmune disease. These findings may open up novel therapeutic avenues where fine-tuning of FCGR2A levels may constitute a part of treatment strategies for immune-mediated diseases.

Identifiants

DOI: 10.1093/hmg/ddab372 PMID: 34970970 PMC: PMC9239749
pubmed: 34970970
pii: 6490623
doi: 10.1093/hmg/ddab372
pmc: PMC9239749
doi:

Substances chimiques

FCGR2A protein, human 0
Receptors, IgG 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1946-1961

Subventions

Organisme : NHGRI NIH HHS
ID : R01 HG008131
Pays : United States
Organisme : NHGRI NIH HHS
ID : R00HG009917
Pays : United States

Informations de copyright

© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Références

Chest. 2012 Dec;142(6):1474-1481
pubmed: 22628489
Blood. 2016 Mar 3;127(9):1097-101
pubmed: 26764357
Cytometry A. 2019 Feb;95(2):150-155
pubmed: 30549419
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
J Immunol. 2006 Dec 15;177(12):8440-7
pubmed: 17142741
Nat Immunol. 2019 Jul;20(7):902-914
pubmed: 31209404
Nat Commun. 2020 Mar 6;11(1):1237
pubmed: 32144282
Blood. 2009 Apr 16;113(16):3716-25
pubmed: 19018092
Nat Commun. 2021 Feb 3;12(1):772
pubmed: 33536424
Bioinformatics. 2016 Aug 15;32(16):2473-80
pubmed: 27153628
Nat Protoc. 2014 Jan;9(1):171-81
pubmed: 24385147
Bioinformatics. 2007 Jan 15;23(2):134-41
pubmed: 17098775
Science. 2016 Nov 11;354(6313):769-773
pubmed: 27708057
Am J Hum Genet. 2013 Jan 10;92(1):28-40
pubmed: 23261299
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Nat Med. 2020 Mar;26(3):333-340
pubmed: 32066974
Genes Immun. 2015 Sep;16(6):422-9
pubmed: 26133275
Inflammation. 2016 Apr;39(2):518-25
pubmed: 26490967
Mol Cell. 2017 Sep 21;67(6):1049-1058.e6
pubmed: 28938092
J Clin Invest. 2005 Feb;115(2):407-17
pubmed: 15668740
Cell. 2014 Dec 18;159(7):1665-80
pubmed: 25497547
J Investig Allergol Clin Immunol. 2019;29(4):251-261
pubmed: 30183655
Nat Methods. 2018 Dec;15(12):992-993
pubmed: 30504875
Cell. 2004 Nov 24;119(5):591-602
pubmed: 15550242
Nat Rev Immunol. 2008 Jan;8(1):34-47
pubmed: 18064051
Annu Rev Microbiol. 1986;40:29-53
pubmed: 2946261
Nucleic Acids Res. 2020 Jan 8;48(D1):D87-D92
pubmed: 31701148
Microbiol Spectr. 2016 Dec;4(6):
pubmed: 28087938
Science. 2014 May 2;344(6183):519-23
pubmed: 24786080
Science. 2015 Nov 27;350(6264):1096-101
pubmed: 26472758
Nat Genet. 2009 Dec;41(12):1313-8
pubmed: 19898481
Bioinformatics. 2013 Feb 15;29(4):461-7
pubmed: 23267174
Nucleic Acids Res. 2013 Jan;41(Database issue):D1040-6
pubmed: 23203888
Nat Methods. 2015 Dec;12(12):1143-9
pubmed: 26501517
Front Immunol. 2018 Jun 22;9:1420
pubmed: 29988341
EMBO Rep. 2018 Dec;19(12):
pubmed: 30413482
Leukemia. 2019 Apr;33(4):945-956
pubmed: 30470836
Science. 2014 Mar 7;343(6175):1246980
pubmed: 24604203
Nat Rev Genet. 2014 Apr;15(4):272-86
pubmed: 24614317
Genome Biol. 2018 Oct 4;19(1):151
pubmed: 30286773
Nat Commun. 2019 Sep 6;10(1):4063
pubmed: 31492858
Nature. 2015 Nov 12;527(7577):192-7
pubmed: 26375006
Science. 2016 Sep 30;353(6307):1545-1549
pubmed: 27708104
J Immunol. 1991 Aug 15;147(4):1338-43
pubmed: 1831223
Nat Genet. 2011 Nov 13;43(12):1241-6
pubmed: 22081228
Cell. 2013 Feb 28;152(5):1173-83
pubmed: 23452860
Mol Cell. 2017 Sep 21;67(6):1037-1048.e6
pubmed: 28890333
Elife. 2016 Sep 23;5:
pubmed: 27661255
Bioinformatics. 2009 Jan 15;25(2):167-74
pubmed: 19017655
Atherosclerosis. 2009 Aug;205(2):512-6
pubmed: 19232413
Front Immunol. 2015 Feb 24;6:79
pubmed: 25759693
Ann Rheum Dis. 2015 Mar;74(3):e13
pubmed: 24532676
Nat Genet. 2010 Apr;42(4):332-7
pubmed: 20228799
Antioxid Redox Signal. 2002 Feb;4(1):85-95
pubmed: 11970846
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
Cell. 2013 Jul 18;154(2):442-51
pubmed: 23849981
Nat Biotechnol. 2019 Mar;37(3):224-226
pubmed: 30809026
Cell. 2019 Jan 10;176(1-2):377-390.e19
pubmed: 30612741
Epigenetics. 2014 Feb;9(2):276-85
pubmed: 24213554
Arthritis Rheum. 1995 Dec;38(12):1832-6
pubmed: 8849356
Nat Genet. 2015 Dec;47(12):1457-1464
pubmed: 26502338
Science. 2014 Sep 12;345(6202):1254665
pubmed: 25214635
J Am Coll Cardiol. 2018 Jul 10;72(2):237-238
pubmed: 29976297
Nat Genet. 2019 Dec;51(12):1664-1669
pubmed: 31784727
Cell. 2014 Oct 23;159(3):647-61
pubmed: 25307932
Am J Hum Genet. 2005 Jan;76(1):8-32
pubmed: 15549674
Cell. 2007 Mar 23;128(6):1231-45
pubmed: 17382889
J Leukoc Biol. 1998 Apr;63(4):405-17
pubmed: 9544570
Cell. 2018 Oct 4;175(2):598-599
pubmed: 30290144
Immunol Res. 2007;39(1-3):271-8
pubmed: 17917071
Genome Biol. 2016 Apr 28;17:77
pubmed: 27121950
Cell. 2015 Apr 9;161(2):387-403
pubmed: 25772697
Am J Hum Genet. 2012 Jun 8;90(6):973-85
pubmed: 22608500
Kidney Int. 2007 Apr;71(7):664-72
pubmed: 17332738
Trends Cell Biol. 2014 Nov;24(11):695-702
pubmed: 25160912

Auteurs

Johanna Dahlqvist (J)

Center for Cell Circuits, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden.
ORCID: 0000-0002-6283-644X

Charles P Fulco (CP)

Center for Cell Circuits, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Bristol Myers Squibb, Cambridge, MA 02142, USA.

John P Ray (JP)

Center for Cell Circuits, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Systems Immunology, Benaroya Research Institute, Seattle, WA 98101, USA.

Thomas Liechti (T)

ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20814, USA.

Carl G de Boer (CG)

Klarman Cell Observatory, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.

David J Lieb (DJ)

Center for Cell Circuits, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

Thomas M Eisenhaure (TM)

Center for Cell Circuits, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

Jesse M Engreitz (JM)

Center for Cell Circuits, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
BASE Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.

Mario Roederer (M)

ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20814, USA.

Nir Hacohen (N)

Center for Cell Circuits, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.

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Classifications MeSH

questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Systematic identification of genomic elements...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Systematic identification of genomic elements...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Éléments activateurs (génétique) › Systematic identification of genomic elements...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Systematic identification of genomic elements...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Systematic identification of genomic elements...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Systematic identification of genomic elements...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteur Fc › Récepteurs du fragment Fc des IgG › Systematic identification of genomic elements...