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LILRB1 Intron 1 Has a Polymorphic Regulatory Region That Enhances Transcription in NK Cells and Recruits YY1

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LILRB1 Intron 1 Has a Polymorphic Regulatory Region That Enhances Transcription in NK Cells and Recruits YY1 LILRB1 Intron 1 Has a Polymorphic Regulatory Region That Enhances Transcription in NK Cells and Recruits YY1 This information is current as Kang Yu, Chelsea E. Davidson and Deborah N. Burshtyn of October 1, 2021. J Immunol published online 22 April 2020 http://www.jimmunol.org/content/early/2020/04/21/jimmun ol.2000164 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/04/21/jimmunol.200016 Material 4.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published April 22, 2020, doi:10.4049/jimmunol.2000164 The Journal of Immunology LILRB1 Intron 1 Has a Polymorphic Regulatory Region That Enhances Transcription in NK Cells and Recruits YY1 Kang Yu,* Chelsea E. Davidson,*,1 and Deborah N. Burshtyn*,†,‡ LILRB1 is a highly polymorphic receptor expressed by subsets of innate and adaptive immune cells associated with viral and autoimmune diseases and targeted by pathogens for immune evasion. LILRB1 expression on human NK cells is variegated, and the frequency of LILRB1+ cells differs among people. However, little is known about the processes and factors mediating LILRB1 transcription in NK cells. LILRB1 gene expression in lymphoid and myeloid cells arises from two distinct promoters that are separated by the first exon and intron. In this study, we identified a polymorphic 3-kb region within LILRB1 intron 1 that is epigenetically marked as an active enhancer in human lymphoid cells and not monocytes. This region possesses multiple YY1 sites, and complexes of the promoter/enhancer combination were isolated using anti-YY1 in chromatin immunoprecipitation–loop. CRISPR-mediated deletion of the 3-kb region lowers LILRB1 expression in human NKL cells. Together, these results indicate the enhancer in intron 1 binds YY1 and suggest YY1 provides a scaffold function enabling enhancer function in regulating LILRB1 Downloaded from gene transcription in human NK cells. The Journal of Immunology, 2020, 204: 000–000. he human leukocyte Ig-like receptors (LILRs) family has One of the most highly studied LILR is LILRB1, an inhibitory 11 multifunctional regulatory receptors involved in im- receptor for which genetic variation has been linked to various mune tolerance, inflammation, hematopoietic differenti- autoimmune conditions, including rheumatoid arthritis, systemic T http://www.jimmunol.org/ ation, and neural functions. LILRs are widely expressed within the lupus erythematosus, and atherosclerosis (6–13). LILRB1 is expressed immune system and interact with diverse ligands ranging from on monocytes, dendritic cells, B cells, and subsets of T and NK cells MHC class I (MHC-I) molecules, CNS-derived molecules, and host (2, 14, 15). LILRB1 regulates cellular responses through binding immune-modulatory proteins to pathogen-derived molecules and classical and nonclassical MHC-I molecules (4, 16) as well as intact pathogens (1). The LILR family contains stimulatory recep- S100A9 (17). LILRB1 is exploited by several bacteria, viruses, tors that transmit signals through associated signaling subunits and and parasites that interact directly with LILRB1, such as dengue inhibitory receptors that repress signaling through ITIMs within virus, malaria, and human CMV (HCMV) (14, 18, 19). For ex- their cytoplasmic tails. The family is characterized by substantial ample, HCMV expresses an MHC-I mimic named UL18 that binds polymorphism and copy number variation, and the genetic diversity tightly to LILRB1 (14, 20). The presumed main function of UL18 by guest on October 1, 2021 has been linked to disease susceptibility (2–4). Each family member is to inhibit NK cell responses. LILRB1-negative NK cells control displays a unique expression pattern on immune cells and can be virus dissemination in vitro better than LILRB1+ NK cells (21– constitutively expressed or induced under particular conditions (5). 23). LILRB1 is the only LILR expressed on NK cells, and its expression is variegated. Moreover, the frequency of LILRB1+ NK cells differs among individuals. HCMV infection is also as- *Department of Medical Microbiology and Immunology, University of Alberta, sociated with the expansion of LILRB1+ NK cells, and LILRB1 Edmonton, Alberta T6G 2S2, Canada; †Alberta Transplant Institute, University of Alberta, Edmonton, Alberta T6G 2H7, Canada; and ‡Li Ka Shing Institute of Virol- expression on other lymphoid cells can fluctuate with time, par- ogy, University of Alberta, Edmonton, Alberta T6G 2H7, Canada ticularly in response to HCMV replication (21, 24–26). We re- 1Current address: College of Veterinary Science, University of Saskatchewan, Sas- cently described that LILRB1 polymorphisms correlated with katoon, Saskatchewan, Canada. LILRB1 expression patterns on NK cells are also correlated with ORCID: 0000-0003-4829-3351 (D.N.B.). the control of HCMV in transplant patients (27). Received for publication February 14, 2020. Accepted for publication March 31, Although the precise mechanism underlying variegated LILRB1 2020. expression in NK cells and the variation in the LILRB1+ NK cell This work was supported by Canadian Institutes of Health Research Grants frequency are not known, we and others have linked particular MOP123257 and PJT162372 (awarded to D.N.B.). K.Y. was funded by studentships + from the China Scholarship Council and a University of Alberta Faculty of Medicine haplotypes with the frequency of LILRB1 NK cells (28, 29), a and Dentistry 75th Anniversary Award. C.E.D. was supported by scholarships from feature reminiscent of the expression patterns of the highly related the Natural Sciences and Engineering Research Council of Canada and Alberta and syntenic killer-cell Ig-like receptors (KIRs). For example, Innovates Health Solutions. KIRs have allele-specific expression patterns (30), and KIR ex- Address correspondence and reprint requests to Dr. Deborah Burshtyn, Department of Medical Microbiology and Immunology, 6-020 Katz Research Centre, University pression is acquired at a late stage of NK differentiation as is of Alberta, Edmonton, AB T6G 2S2, Canada. E-mail address: [email protected] LILRB1 (31). The KIR expression patterns are correlated with The online version of this article contains supplemental material. DNA methylation at the promoter region (32–34), and there is Abbreviations used in this article: BAC, bacterial artificial chromosome; 3C, chro- evidence that DNA methylation is involved in keeping LILR mosome conformation capture; C/EBP, Ccaat-enhancer-binding protein; ChIP, chro- genes quiescent (35). During NK development, a probabilistic matin immunoprecipitation; ChIP-Seq, ChIP sequencing; ddPCR, Droplet Digital PCR; GEO, Gene Expression Omnibus; HCMV, human CMV; KIR, killer-cell Ig- switch controls expression of KIR through a bidirectional pro- like receptor; LILR, leukocyte Ig-like receptor; LINE, long interspersed nuclear moter for which the relative strength of the forward activity over element; MHC-I, MHC class I; qPCR, quantitative PCR; SNP, single-nucleotide the reverse activity correlates with the frequency of a particular of polymorphism; YY1, Yin Yang 1. KIR gene progressing to permanent expression (36, 37). Poly- Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 morphisms within the bidirectional promoter are associated with www.jimmunol.org/cgi/doi/10.4049/jimmunol.2000164 2 LILRB1 INTRON 1 ENHANCER allele-specific frequencies of expression for a given KIR gene (30, cells from each LILRB1+ clone were lysed using the SingleShot Cell Lysis 38). Although multiple KIR genes can be expressed in a single NK Kit (Bio-Rad, Hercules, CA) following the manufacturer’s protocol and cell, typically only one allele for each KIR gene is expressed, and immediately subjected to reverse transcription using iScript Advanced cDNA Synthesis Kit (Bio-Rad). A custom TaqMan genotyping assay (identifier: a piwi-like system arising from the antisense transcript may si- ANGZE69) was used to differentiate the expression of alleles specific for lence the other allele of a KIR gene that has initiated reverse rs1061079 (C/T) that was designed using the online tool (https://www. transcription (39). The LILRB1 gene has 16 exons, and tran- thermofisher.com/order/custom-genomic-products/tools/genotyping/). The scription is initiated at two distinct promoters (15). The first (59) sequences of primers and probes are listed in Supplemental Table I. Each Droplet Digital PCR (ddPCR) reaction was prepared by mixing the cDNA promoter is used by lymphoid cells, and the resulting transcript template derived from ∼1000 cells of every single clone, TaqMan primers has all 16 exons (15). We previously defined the core region of the probes mix, and ddPCR Supermix
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