CDEFAGHThe majority of the disease-susceptibility genetic variants revealed by ge-0.90.70.50.30.129CAGE ‐CAGE +Interaction between enhancer and promoterRisk SNPenhancerPromoter/enhancer QTLATAC‐QTLHistone‐QTLexpression‐QTL (eQTL)promoterGWAS VariantsMulti‐omics data from each cell typeBCAGEsequencing:enhancer/promoterATAC‐seq:open chromatin ChIP‐seq:modified histones RNA‐Seq:gene expression levelsMicroC‐seq:3D‐chromatin interactionIntegrated multi‐omics dataGenomic Landscape by interpretation of multi‐omics dataFigure: Functional genetics of autoimmune dis-easesnome-wide association study (GWAS) function as expression quantitative trait loci (eQTLs) that are involved in gene expression. The eQTL effect is fre-quently found in a cell type-specific manner. Such cell specificity is largely due to epigenomic alterations, such as cell type-specific histone modifications and DNA methylation in specific regions of chromosomes. It has been further re-ported that disease susceptibility variants significantly overlap with the location of histone modifications in promoters and active enhancers of specific immune cell subsets. Therefore, it is possible to provide causal information to the inter-mediate phenotypes between genetic information and disease by qualitatively and quantitatively measuring the functional molecules of immunocompetent cells in various immunological diseases, focusing on disease-susceptible genetic variants, gene expression (mRNA), epigenome, and proteins.We are performing functional genomic strategies for integrating GWAS results with the current understanding of specific diseases, mainly focusing on promoters, enhancers, and long non-coding RNAs. We are isolating nearly 30 different lymphocyte subsets from human peripheral blood mononuclear cells of healthy individuals and analyzing genotypes, gene expression, and open chromatin regions. Cells from healthy individuals are expected to exhibit the least biased gene expression and thus can provide a baseline for comparison with cells from patients with immunological diseases. Since chromosomes are transmitted to offspring in certain blocks and many neighboring genetic vari-ants behave similarly, it is not easy to determine which among them is the true causal variant. Using several methods including CAGE analysis, we are tracking down the targets.We are also performing several analyses using recently developed single-cell technologies. By integrating these fragments of information, we can understand the physiological and pathological changes of the whole immune system of an individual and the ways for intervening when there are unfavorable conditions.Recent Major PublicationsSakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, Narita A, Konuma T, Yamamoto K, Akiyama M, Ishigaki K, Suzuki A, Suzuki K, Obara W, Yamaji K, Taka-hashi K, Asai S, Takahashi Y, Suzuki T, Shinozaki N, Yama-guchi H, Minami S, Murayama S, Yoshimori K, Nagayama S, Obata D, Higashiyama M, Masumoto A, Koretsune Y, FinnGen; Ito K, Terao C, Yamauchi T, Komuro I, Kadowaki T, Tamiya G, Yamamoto M, Nakamura Y, Kubo M, Mu-rakami Y, Yamamoto K, Kamatani Y, Palotie A, Rivas MA, Daly MJ, Matsuda K, Okada Y. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet 53, 1415-1424 (2021)Ota M, Nagafuchi Y, Hatano H, Ishigaki K, Terao C, Takeshima Y, Yanaoka H, Kobayashi S, Okubo M, Shirai H, Sugimori Y, Maeda J, Nakano M, Yamada S, Yoshida R, Tsuchiya H, Tsuchida Y, Akizuki S, Yoshifuji H, Ohmura K, Mimori T, Yoshida K, Kurosaka D, Okada M, Setoguchi K, Kaneko H, Ban N, Yabuki N, Matsuki K, Mutoh H, Oyama S, Okazaki M, Tsunoda H, Iwasaki Y, Sumitomo S, Shoda H, Kochi Y, Okada Y, Yamamoto K, Okamura T, Fujio K. Dynamic landscape of immune cell-specific gene regula-tion in immune-mediated diseases. Cell 184, 3006-3021 (2021)Suzuki A, Guerrini MM, Yamamoto K. Functional genom-ics of autoimmune diseases. Ann Rheum Dis 80, 689-697 (2021)Invited presentationsYamamoto K. “Dynamic Landscape of immune cell-specific gene regulation” The 13th International Forum on Rheumatoid Arthritis (IFRA2021) (Beijing, China/Online) September 2021Laboratory for Autoimmune DiseasesTeam Leader: Kazuhiko Yamamoto
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