HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region Nicolas Vince, Hongchuan Li, Veron Ramsuran, Vivek Naranbhai,

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HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region Nicolas Vince, Hongchuan Li, Veron Ramsuran, Vivek Naranbhai, Fuh-Mei Duh, Benjamin P. Fairfax, Bahara Saleh, Julian C. Knight, Stephen K. Anderson, Mary Carrington The American Journal of Human Genetics Volume 99, Issue 6, Pages 1353-1358 (December 2016) DOI: 10.1016/j.ajhg.2016.09.023 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 HLA-C Level Is Associated with rs2395471 in the Promoter Region of HLA-C (A) Association between SNPs located in a 200 kb window around HLA-C and imputed HLA-C level. The Manhattan plot was created with LocusZoom.15 Each dot represents a SNP for which the color depicts the linkage disequilibrium (LD) score (r2) computed with PLINK16 in the European 1KG dataset (n = 228). A complete list of LD scores between rs2395471 and the surrounding 1 Mb SNPs is presented in Table S2. Logistic regression tests for association between the 68,726 SNPs in the HLA locus and HLA-C level was performed in R (version 3.2.4) using the imputed HLA-C level values as a continuous variable. (B) A list of HLA-C lineages that carry either the A or G at the rs2395471 SNP and a map of the HLA-C promoter region are shown. The American Journal of Human Genetics 2016 99, 1353-1358DOI: (10.1016/j.ajhg.2016.09.023) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Association between rs2395471 and HLA-C Cell Surface Level Cell surface level was measured directly in two independent cohorts of (A) 195 African Americans and (B) 174 European Americans. HLA-C cell surface level was measured on CD3+ cells from peripheral blood by flow cytometry. For each plot, the p value from linear regression and R2 (the level of variation explained by the SNP) are provided. The rs2395471 genotypes were determined by Sanger sequencing. The mean with standard deviation is represented. The National Health Institutes office of human subjects research protection approved this study. The American Journal of Human Genetics 2016 99, 1353-1358DOI: (10.1016/j.ajhg.2016.09.023) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 The Oct1 Transcription Factor Binds to the Genomic Region Containing rs2395471 Electrophoretic mobility shift assay (EMSA) was performed using nuclear protein extract from HeLa cell line (A and B) and PBMCs (C). Two oligonucleotides were designed, one containing the rs2395471_G allele and one containing the rs2395471_A allele (detailed methods can be found in Li et al.,22 primers are available upon request). (A) The presence of a shift (arrow) indicates that the genomic region containing rs2395471 binds a protein from the HeLa nuclear extract. A supershift is observed when anti-Oct1 antibodies (2 different clones) are added, but not anti-Oct2, anti-Oct3/4, or anti-Sp1 antibodies, indicating that Oct1 is a transcription factor that binds to the rs2395471 genomic region. (B) HeLa nuclear extract binds to oligonucleotides containing rs2395471_A more strongly than it does to rs2395471_G. (C) Nuclear proteins derived from PBMCs of two donors were extracted and incubated with the oligonucleotides and antibodies to anti-Oct1 and anti-Oct3/4. A supershift was detected only in the presence of the anti-Oct1 antibody, confirming the specificity of this TF binding site for Oct1. The American Journal of Human Genetics 2016 99, 1353-1358DOI: (10.1016/j.ajhg.2016.09.023) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 4 Impact of the rs2395471 on the HLA-C Promoter Activity Estimated by Luciferase Assay The HLA-C promoters of two alleles carrying rs2395471_A, C∗01:02 and C∗04:01, and two alleles carrying rs2395471_G, C∗03:04 and C∗08:02, were cloned in a pGL3 plasmid. We mutated this position by site-directed mutagenesis to obtain new plasmids with a G nucleotide at the rs2395471 position for C∗01:02 and C∗04:01 and an A at this position for C∗03:04 and C∗08:02 (detailed methods can be found in Li et al.,22 primers are available upon request). Both HLA-C∗01:02 and C∗04:01 promoters in which rs2395471_A was mutated to rs2395471_G show a significant decrease in promoter activity. Both HLA-C∗03:04 and C∗08:02 promoters in which rs2395471_G was mutated to rs2395471_A show no significant difference in promoter activity. Two-way ANOVA. ∗∗p < 0.01, ∗∗∗∗p < 0.0001. WT: wild-type. The mean of four replicated experiments with standard error is represented. The American Journal of Human Genetics 2016 99, 1353-1358DOI: (10.1016/j.ajhg.2016.09.023) Copyright © 2016 American Society of Human Genetics Terms and Conditions