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Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development

Aaron R. Victor, Christoph Weigel, Steven D. Scoville, Wing Keung Chan, Kelsey Chatman, Mary M. Nemer, Charlene Mao, Karen A. Young, Jianying Zhang, Jianhua Yu, Aharon G. Freud, Christopher C. Oakes and Michael A. Caligiuri
J Immunol January 15, 2018, 200 (2) 565-572; DOI: https://doi.org/10.4049/jimmunol.1701128
Aaron R. Victor
Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210;The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
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Christoph Weigel
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
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Steven D. Scoville
Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210;The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
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Wing Keung Chan
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
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Kelsey Chatman
College of Medicine, The Ohio State University, Columbus, OH 43210;
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Mary M. Nemer
College of Medicine, The Ohio State University, Columbus, OH 43210;
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Charlene Mao
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
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Karen A. Young
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;
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Jianying Zhang
Center for Biostatistics, Department of Bioinformatics, The Ohio State University, Columbus, OH 43210;
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Jianhua Yu
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
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Aharon G. Freud
Department of Pathology, The Ohio State University, Columbus, OH 43210;
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Christopher C. Oakes
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210; and
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Michael A. Caligiuri
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210
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Abstract

The surface receptor FcγRIIIA (CD16a) is encoded by the FCGR3A gene and is acquired by human NK cells during maturation. NK cells bind the Fc portion of IgG via CD16a and execute Ab-dependent cell-mediated cytotoxicity, which is critical for the effectiveness of several antitumor mAb therapies. The role of epigenetic regulatory mechanisms controlling transcriptional and posttranscriptional CD16 expression in NK cells is unknown. In this study, we compared specific patterns of DNA methylation and expression of FCGR3A with FCGR3B, which differ in cell type–specific expression despite displaying nearly identical genomic sequences. We identified a sequence within the FCGR3A promoter that selectively exhibits reduced methylation in CD16a+ NK cells versus CD16a− NK cells and neutrophils. This region contained the transcriptional start site of the most highly expressed CD16a isoform in NK cells. Luciferase assays revealed remarkable cell-type specificity and methylation-dependent activity of FCGR3A- versus FCGR3B-derived sequences. Genomic differences between FCGR3A and FCGR3B are enriched at CpG dinucleotides, and mutation of variant CpGs reversed cell-type specificity. We further identified miR-218 as a posttranscriptional negative regulator of CD16a in NK cells. Forced overexpression of miR-218 in NK cells knocked down CD16a mRNA and protein expression. Moreover, miR-218 was highly expressed in CD16a− NK cells compared with CD16a+ NK cells. Taken together, we propose a system of FCGR3A regulation in human NK cells in which CpG dinucleotide sequences and concurrent DNA methylation confer developmental and cell type–specific transcriptional regulation, whereas miR-218 provides an additional layer of posttranscriptional regulation during the maturation process.

This article is featured in In This Issue, p.373

Footnotes

  • ↵2 C.C.O. and M.A.C. are cosenior authors.

  • This work was supported by the National Institutes of Health (Grants CA095426, CA210087, CA163205, CA199447, CA068458, and CA09338) and by the Ohio State University Comprehensive Cancer Center.

  • The microarray data presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo) under accession number GSE106469.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    ADCC
    Ab-dependent cell-mediated cytotoxicity
    ATCC
    American Type Culture Collection
    miRNA
    microRNA
    NKDI
    NK cell developmental intermediate
    Pmed1
    medial promoter-1
    Pprox
    proximal promoter
    rhIL-2
    recombinant human IL-2
    SLT
    secondary lymphoid tissue
    UTR
    untranslated region.

  • Received August 7, 2017.
  • Accepted November 6, 2017.
  • Copyright © 2018 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 200 (2)
The Journal of Immunology
Vol. 200, Issue 2
15 Jan 2018
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Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development
Aaron R. Victor, Christoph Weigel, Steven D. Scoville, Wing Keung Chan, Kelsey Chatman, Mary M. Nemer, Charlene Mao, Karen A. Young, Jianying Zhang, Jianhua Yu, Aharon G. Freud, Christopher C. Oakes, Michael A. Caligiuri
The Journal of Immunology January 15, 2018, 200 (2) 565-572; DOI: 10.4049/jimmunol.1701128

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Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development
Aaron R. Victor, Christoph Weigel, Steven D. Scoville, Wing Keung Chan, Kelsey Chatman, Mary M. Nemer, Charlene Mao, Karen A. Young, Jianying Zhang, Jianhua Yu, Aharon G. Freud, Christopher C. Oakes, Michael A. Caligiuri
The Journal of Immunology January 15, 2018, 200 (2) 565-572; DOI: 10.4049/jimmunol.1701128
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Print ISSN 0022-1767        Online ISSN 1550-6606