title: The DNA methylation profile of activated human natural killer cells.
abstract: Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in naïve NK, T- and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.
authors.affiliation: a Department of Neurological Surgery , University of California San Francisco , San Francisco , CA.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.affiliation: b Brown University , Department of Epidemiology , Providence , RI.
authors.forename: Rondi
authors.initials: R
authors.lastname: Butler
authors.affiliation: a Department of Neurological Surgery , University of California San Francisco , San Francisco , CA.
authors.forename: George
authors.initials: G
authors.lastname: Hsuang
authors.affiliation: b Brown University , Department of Epidemiology , Providence , RI.
authors.forename: Melissa
authors.initials: M
authors.lastname: Eliot
authors.affiliation: b Brown University , Department of Epidemiology , Providence , RI.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kim
authors.affiliation: d Janssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson , 1400 Welsh and McKean Roads, Spring House , PA.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Sepulveda
authors.affiliation: d Janssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson , 1400 Welsh and McKean Roads, Spring House , PA.
authors.forename: Derick
authors.initials: D
authors.lastname: Siegel
authors.affiliation: e University of Oregon, College of Public Health and Human Science , Corvallis , OR.
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.affiliation: b Brown University , Department of Epidemiology , Providence , RI.|c Department of Laboratory Medicine and Pathology , Providence , RI.
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000276:immunology; D001782:Blood Donors; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000276:immunology; D019175:DNA Methylation / Q000235:genetics* / Q000276:immunology; D044127:Epigenesis, Genetic / Q000235:genetics* / Q000276:immunology; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D011401:Promoter Regions, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D018398:Homeodomain Proteins; C107989:BHLHE40 protein, human
keywords: DNA methylation; Differentially methylated regions; NK cells; NKp46; digital PCR; innate immunity