Browsing by Subject "Interferon Regulatory Factors"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    BATF-Interacting Proteins Dictate Specificity in Th Subset Activity
    (American Association of Immunologists, 2020-10-01) Fu, Yongyao; Koh, Byunghee; Kuwahara, Makoto; Ulrich, Benjamin J.; Kharwadkar, Rakshin; Yamashita, Masakatsu; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    The basic leucine zipper (bZIP) transcription factor BATF is expressed in multiple Th subsets and cooperates with other factors to regulate gene transcription. BATF activates lineage-specific cytokines in Th subsets, activating IL-9 in Th9 cells and IL-17 in Th17 cells, but not IL-9 or IL-17 in the reciprocal subset. The mechanism for this restricted activity is unclear. In this report we define BATF binding partners that contribute to Th subset-specific functions. Although BATF and IRF4 are expressed in greater amounts in Th9 than Th17, increased expression of both factors is not sufficient to induce IL-9 in Th17 cells. BATF also requires heterodimer formation with Jun family members to bind DNA and induce gene expression. Using primary mouse T cell culture, we observed that JunB and c-Jun, but not JunD, promote IL-9 production in Th9 cells. Ectopic expression of BATF with either JunB or c-Jun generates modest but significant increases in IL-9 production in Th17 cells, suggesting that the low expression of Jun family members is one factor limiting the ability of BATF to induce IL-9 in Th17 cells. We further identified that Bach2 positively regulates IL-9 production by directly binding to the Il9 gene and by increasing transcription factor expression in Th9 cells. Strikingly, co-transduction of Bach2 and BATF significantly induces IL-9 production in both Th9 and Th17 cells. Taken together, our results reveal that JunB, c-Jun and Bach2 cooperate with BATF to
  • Thumbnail Image
    Item
    Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
    (Cold Spring Harbor Laboratory Press, 2018-11) Zhang, Tongwu; Choi, Jiyeon; Kovacs, Michael A.; Shi, Jianxin; Xu, Mai; Goldstein, Alisa M.; Trower, Adam J.; Bishop, D. Timothy; Iles, Mark M.; Duffy, David L.; MacGregor, Stuart; Amundadottir, Laufey T.; Law, Matthew H.; Loftus, Stacie K.; Pavan, William J.; Brown, Kevin M.; Epidemiology, School of Public Health
    Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4 Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
  • Thumbnail Image
    Item
    Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis
    (Springer Nature, 2018-08) Kowalec, Kaarina; Wright, Galen E.B.; Drögemöller, Britt I.; Aminkeng, Folefac; Bhavsar, Amit P.; Kingwell, Elaine; Yoshida, Eric M.; Traboulsee, Anthony; Marrie, Ruth Ann; Kremenchutzky, Marcelo; Campbell, Trudy L.; Duquette, Pierre; Chalasani, Naga; Wadelius, Mia; Hallberg, Pär; Xia, Zongqi; Jager, Philip L. De; Denny, Joshua C.; Davis, Mary F.; Ross, Colin J.D.; Tremlett, Helen; Carleton, Bruce C.; Medicine, School of Medicine
    Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10-8, odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10-5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use.