2_PAMUnnw2_PAMUnnw50505005wnnUMAP_15wnnUMAP_1Gene regulation is one of the most fundamental mechanisms governing cell 61ExpressionActivity−5−10−52.01.51.0−510−10−51010functions and biological processes, including immune cells and the im-mune system, and has been studied in many contexts. Recent advances in epig-enome and transcriptome profiling technologies enable us to investigate gene regulation more comprehensively and precisely than ever to elucidate uncharted mechanisms in biology. Accordingly, transcriptomics has developed as a field of research to challenge biological questions utilizing these profiling approaches in a data-driven manner. In contrast, immunological studies usually start from phenotypes and investigate underlying mechanisms employing a hypothesis-driven approach. As both approaches have their own advantages, integration of immunology and transcriptomics can effectively dissect the immune system in an unprecedented manner. We are utilizing the techniques of cutting-edge transcriptomics to dissect gene regulation in immune cells, which will provide a deeper understanding of immune cell functions and ultimately lead to advances in the treatment of immune disorders. While transcriptomic approaches can be applied for various studies, we are currently engaging two major subjects.1) Gene regulation underpinning immune tolerance.Negative selection of self-reactive T cells occurs in the thymus and is an essential mechanism for achieving immune tolerance. Thymic medullary epi-thelial cells (mTECs) express various self-antigens, including peripheral tissue antigens (PTAs), whose expression is otherwise restricted to specific peripheral tissues. Developing T cells that strongly react with self-antigens are eliminated by apoptosis. Since the disrupted expression of PTAs can result in disturbed negative selection and autoimmune disorders, understanding the mechanisms controlling their expression is important to understand the pathogenesis of au-toimmune diseases and to develop new treatments. To thoroughly understand mTECs and PTA expression, we have analyzed mTECs by single-cell RNA-seq and revealed gene regulation and populational heterogeneity (Figure). We are now investigating the immunological significance of our findings by transcrip-tomic approaches employing mouse models.2) Data-driven project: systematic analysis of various immunocytes.Bioinformatics has greatly impacted research on gene regulation and is be-coming more powerful with the advent of big data analysis. To promote these data-driven studies, we are collaborating with the worldwide ImmGen group (http://www.immgen.org/).Figure: Activity of a transcription factor (TF) associated with a subpopulation of mTECsTF expression and activity were examined by single-cell profiling and are shown for a representative TF by a color gradient (expression, left panel; activity, right panel). While TF activity does not always correlate with its expression, this TF is active in the expressed population. As a TF specific for a population can relate to its identity and function, this information is helpful to understand the population.Recent Major PublicationsMorimoto J, Matsumoto M, Miyazawa R, Yoshida H, Tsuneyama K, Matsumoto M. Aire suppresses CTLA-4 expression from the thymic stroma to control autoim-munity. Cell Rep 38, 110384 (2022)Nishijima H, Matsumoto M, Morimoto J, Hosomichi K, Akiyama N, Akiyama T, Oya T, Tsuneyama K, Yoshida H, Matsumoto M. Aire Controls Heterogeneity of Medul-lary Thymic Epithelial Cells for the Expression of Self-Antigens. J Immunol 208, 303-320 (2022)Rose SA, Wroblewska A, Dhainaut M, Yoshida H, Shaffer JM, Bektesevic A, Ben-Zvi B, Rhoads A, Kim EY, Yu B, Lavin Y, Merad M, Buenrostro JD, Brown BD, Immunolog-ical Genome C. A microRNA expression and regulatory element activity atlas of the mouse immune system. Nat Immunol 22, 914-927 (2021)Yoshida H, Lareau CA, Ramirez RN, Rose SA, Maier B, Wroblewska A, Desland F, Chudnovskiy A, Mortha A, Dominguez C, Tellier J, Kim E, Dwyer D, Shinton S, Nabekura T, Qi Y, Yu B, Robinette M, Kim KW, Wagers A, Rhoads A, Nutt SL, Brown BD, Mostafavi S, Buenrostro JD, Benoist C, Immunological Genome P. The cis-Regula-tory Atlas of the Mouse Immune System. Cell 176, 897-912. e20 (2019)Invited presentationsYoshida H. “Transcriptional and post-transcriptional regulatory networks in immunity.” The 94th Annual Meeting of the Japanese Biochemical Society (Japan/Online) November 2021Yoshida H. “Data-driven immunology: analysis of regu-latory mechanisms in immunocytes by comprehensive profiling.” The 29th Molecular Immunology Forum Tokyo (Online) March 2021YCI Laboratory for Immunological TranscriptomicsYoung Chief Investigator: Hideyuki Yoshida
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