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

Dahlqvist, Johanna, 1979- (author)
Uppsala universitet,Institutionen för medicinska vetenskaper,Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Fulco, Charles P (author)
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA;Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Ray, John P (author)
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
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Liechti, Thomas (author)
ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20814, USA
de Boer, Carl G (author)
Klarman Cell Observatory, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA;School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
Lieb, David J (author)
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Eisenhaure, Thomas M (author)
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Engreitz, Jesse M (author)
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Roederer, Mario (author)
ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20814, USA
Hacohen, Nir (author)
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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 (creator_code:org_t)
2021-12-31
2021
English.
In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083.
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

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