Gene regulation is one of the most elemental mechanisms governing cell LTHSC.34−.BMLTHSC.34+.BMSTHSC.150−.BMMMP4.135+.BMproB.CLP.BMproB.FrA.BMproB.FrBC.BMpreB.FrD.BMB.FrE.BMB1b.PCB.T1.SpB.T2.SpB.T3.SpB.MZ.SpB.Fo.SpB.GC.CB.SpB.GC.CC.SpB.PB.SpB.PC.SpB.PC.BMB.mem.SpB.Fem.SpB.SppreT.DN1.ThpreT.DN2a.ThpreT.DN2b.ThpreT.DN3.ThT.DN4.ThT.ISP.ThT.DP.ThT.4.ThT.8.ThT.4.Nve.SpT.4.Nve.Fem.SpT.4.Sp.aCD3+CD40.18hrTreg.4.FP3+.Nrplo.CoTreg.4.25hi.SpT.8.Nve.SpT8.TN.P14.SpT8.IEL.LCMV.d7.GutT8.TE.LCMV.d7.SpT8.MP.LCMV.d7.SpT8.Tcm.LCMV.d180.SpT8.Tem.LCMV.d180.SpNKT.SpNKT.Sp.LPS.3hrNKT.Sp.LPS.18hrNKT.Sp.LPS.3dTgd.g2+d17.24a+.ThTgd.g2+d17.LNTgd.g2+d1.24a+.ThTgd.g2+d1.LNTgd.g1.1+d1.24a+.ThTgd.g1.1+d1.LNTgd.SpNK.27+11b−.BMNK.27+11b+.BMNK.27−11b+.BMNK.27+11b−.SpNK.27+11b+.SpNK.27−11b+.SpILC2.SIILC3.NKp46−CCR6−.SIILC3.NKp46+.SIILC3.CCR6+.SIMMP3.48+.BMGN.BMGN.SpGN.Thio.PCMo.6C+II−.BlMo.6C−II−.BlMF.pIC.Alv.LuMF.226+II+480lo.PCMF.ICAM+480hi.PCMF.RP.SpMF.SI.LPMF.Alv.LuMF.microglia.CNSMF.PCMF.Fem.PCDC.4+.SpDC.8+.SpDC.pDC.SpDC.103+11b+.SIDC.103+11b−.SIFRC.CD140a+.Madcam−.CD35−.SLNIAP.SLNBEC.SLNLEC.SLNEp.MEChi.Th58HprtCd19Cd8afunctions 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, which take advantage of next-generation sequencing (NGS), enable us to investigate gene regulation in an unprecedented manner and, hence, the uncharted mechanisms in biology and immunology are now becoming approachable. 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. Transcriptomic approaches can be ap-plied to various studies in immunological settings and we have been engaged in 1) a focused subject and 2) a data-driven project for a systematic approach.1) Focused subject: gene regulation in immune tolerance.Negative selection of self-reactive T cells occurs in the thymus and is one of the most essential mechanisms to achieve immune tolerance. Thymic medul-lary epithelial cells (TECs) express peripheral tissue antigens (PTAs), whose ex-pression was expected to be restricted to specific peripheral tissues. Developing T cells that strongly react with a PTA are eliminated by apoptosis. Since the dis-rupted expression of PTAs results in severe autoimmune disorders, understand-ing the mechanisms controlling their expression is important to understand the pathogenesis of autoimmune diseases and to develop new treatments. We are analyzing gene expression in TECs by single-cell RNA-seq to examine in detail their gene regulation as well as to define TEC heterogeneity, and then validating these findings by employing mouse models.2) Data-driven project: systematic analysis of various immunocytes.Bioinformatics has greatly impacted gene regulation research 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: Cell type-specific structure of chromatin“Open” and “closed” chromatin in various immune cells was examined by ATAC-seq and is shown by a color gradient (open=red, closed=blue). Since the transcrip-tional regulatory elements are often found in “open” regions, profiling of open chromatin promotes a clearer understanding of the mechanisms of gene regulation. Hprt, housekeeping gene; Cd19, B cell-specific gene; Cd8a, cytotoxic T cell-specific gene. The base of the ar-row under each gene label indicates the transcription start site.Recent Major PublicationsTenno M, Wong AYW, Ikegaya M, Miyauchi E, Seo W, See P, Kato T, Taida T, Oishi-Ohno M, Ohno H, Yoshida H, Ginhoux F, Taniuchi I. Essential functions of Runx/Cbfβ in gut conventional dendritic cells for priming Rorγt+ T cells. Life Sci Alliance 3, e201900441 (2020)Gal-Oz ST, Maier B, Yoshida H, Seddu K, Elbaz N, Czysz C, Zuk O, Stranger BE, Ner-Gaon H, Shay T. ImmGen report: sexual dimorphism in the immune system transcrip-tome. Nat Commun 10, 4295 (2019)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. The cis-Regulatory Atlas of the Mouse Immune System. Cell 176, 897-912 (2019)YCI Laboratory for Immunological TranscriptomicsYoung Chief Investigator: Hideyuki Yoshida
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