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    Mark Ansel, PhD

    TitleAssociate Professor
    SchoolUCSF School of Medicine
    DepartmentMicrobiology and Immunology
    Address513 Parnassus Ave
    San Francisco CA 94143
    Phone415-476-5368

       Overview 
       Overview
      Naive lymphocytes that encounter their cognate antigens differentiate into a variety of immune effector cells under the influence of cytokines and other inflammatory stimuli. Lymphocyte lineage decisions are critical for the development of protective immunity against a great diversity of pathogens, but improper or exaggerated responses also contribute to the development and pathology of autoimmune diseases, chronic inflammation, allergy, and asthma.
      The primary experimental system utilized by the laboratory is the differentiation of helper T cells. Their distinct cellular identities (Th1, Th2, etc.) and associated functions are defined by characteristic gene expression programs. We and many others have documented how these programs are controlled by transcription factors, the cis-regulatory DNA elements to which they bind, and epigenetic modifications that constrain chromatin accessibility at those sites.

      More recently, we found that the endogenous RNA interference (RNAi) pathway also regulates helper T cell differentiation, as naive T cells lacking Dicer exhibit rapid, unrestrained differentiation into effector cells. MicroRNAs (miRNA) are the best-characterized class of natural short regulatory RNAs. As they differentiate, T cells reset their miRNA repertoire. This rapid change in miRNA expression may be important to allow T cells to change their gene expression programs and develop effector functions.

      The major research goals of our laboratory are: i) to define the molecular mechanisms that control miRNA turnover and determine how this process is accelerated in activated lymphocytes; ii) to characterize the expression and function of noncoding RNAs, including miRNAs, in T cell differentiation, and iii) to extend our work beyond in vitro and mouse models to explore how chromatin remodeling and regulatory RNAs contribute to the pathogenic properties of T cells in human asthma.

      MicroRNAs, transcription factors, and epigenetic regulation shape the gene expression programs that determine cell identity and function. The Ansel lab studies how these molecular mechanisms work together to control lymphocyte development, differentiation, and function in immunity.

      We use in vitro cell differentiation systems, mouse genetics, disease models, and high dimensional cellular and molecular analyses in human biospecimens to unravel the regulatory networks that underlie immunity and immune pathology, especially allergy and asthma.

      Lymphocyte lineage decisions and the deployment of their effector functions are critical for the development of protective immunity against a great diversity of pathogens. However, improper or exaggerated responses underlie the pathogenesis of autoimmune diseases, chronic inflammation, allergy, and asthma. Our primary experimental system is the differentiation of helper T cells, the central coordinators of adaptive immune responses. Upon immune activation, naïve CD4+ T cells can differentiate into several different helper T cell effectors subtypes (e.g. Th1, Th2, Th17, iTreg, Tfh, etc.). These lineages are defined by their characteristic gene expression programs and mediate distinct immune functions. These gene expression programs are controlled by external factors that derive from other cells or the environment, signaling-induced and lineage-specific transcription factors, epigenetic regulation of transcriptional responses, and posttranscriptional mechanisms, including RNA-binding proteins and miRNAs. The depth of our knowledge about the networks that control helper T cells makes them an attractive model for studying basic mechanisms of gene regulation.

      Active projects in the laboratory mostly focus on miRNAs. We study how individual miRNA families regulate helper T cell differentiation and immune function, as well as the regulation of the miRNA pathway itself during immune responses. Naive CD4+ T cells that cannot produce any miRNAs exhibit reduced cell division and survival in response to immune stimuli. Surprisingly, they also undergo rapid unrestrained differentiation into effector cells. We have developed a screening technology that allows us to rapidly determine which specific miRNAs regulate each of these T cell behaviors, and a high throughput nanoscaled pipeline for determining miRNA expression patterns in small clinical samples (such as sorted T cell subsets from the airways of human asthmatic subjects, serum, sputum, and other sources of extracellular miRNAs, etc.). In addition, we discovered that T cells rapidly reset their miRNA repertoire upon activation. This process that involves ubiquitination and degradation of Argonaute proteins, but the signaling mechanisms and the fate of associated miRNAs remains unknown. This rapid change in miRNA expression may be important to allow T cells to change their gene expression programs and develop effector functions.


      The major research goals of our laboratory are:

      1) To define the molecular mechanisms that control miRNA homeostasis in lymphocytes, and determine how the miRNA repertoire is so dramatically remodeled during T cell activation.

      2) To characterize the function of individual miRNAs that regulate T cell differentiation and immune effector functions.

      3) To determine how the expression and function of miRNAs contribute to the pathogenic properties of T cells in human asthma.


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       Bibliographic 
       Publications
      Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
      List All   |   Timeline
      1. Baumjohann D, Ansel KM. MicroRNA regulation of the germinal center response. Curr Opin Immunol. 2014 Feb 11; 28C:6-11.
        View in: PubMed
      2. Watchmaker PB, Lahl K, Lee M, Baumjohann D, Morton J, Kim SJ, Zeng R, Dent A, Ansel KM, Diamond B, Hadeiba H, Butcher EC. Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat Immunol. 2014 Jan; 15(1):98-108.
        View in: PubMed
      3. Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol. 2013 Sep; 13(9):666-78.
        View in: PubMed
      4. Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S, de Kouchkovsky D, Bannard O, Bluestone JA, Matloubian M, Ansel KM, Jeker LT. The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol. 2013 Aug; 14(8):840-8.
        View in: PubMed
      5. Ansel KM. RNA regulation of the immune system. Immunol Rev. 2013 May; 253(1):5-11.
        View in: PubMed
      6. Bronevetsky Y, Ansel KM. Regulation of miRNA biogenesis and turnover in the immune system. Immunol Rev. 2013 May; 253(1):304-16.
        View in: PubMed
      7. Baumjohann D, Preite S, Reboldi A, Ronchi F, Ansel KM, Lanzavecchia A, Sallusto F. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity. 2013 Mar 21; 38(3):596-605.
        View in: PubMed
      8. Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, Heinz GA, Kremmer E, Heissmeyer V, McManus MT, Erle DJ, Rao A, Ansel KM. T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire. J Exp Med. 2013 Feb 11; 210(2):417-32.
        View in: PubMed
      9. Hoefig KP, Rath N, Heinz GA, Wolf C, Dameris J, Schepers A, Kremmer E, Ansel KM, Heissmeyer V. Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay. Nat Struct Mol Biol. 2013 Jan; 20(1):73-81.
        View in: PubMed
      10. Seumois G, Vijayanand P, Eisley CJ, Omran N, Kalinke L, North M, Ganesan AP, Simpson LJ, Hunkapiller N, Moltzahn F, Woodruff PG, Fahy JV, Erle DJ, Djukanovic R, Blelloch R, Ansel KM. An integrated nano-scale approach to profile miRNAs in limited clinical samples. Am J Clin Exp Immunol. 2012 Nov 30; 1(2):70-89.
        View in: PubMed
      11. Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, Nguyen C, Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR, Erle DJ, Woodruff PG. Airway epithelial miRNA expression is altered in asthma. Am J Respir Crit Care Med. 2012 Nov 15; 186(10):965-74.
        View in: PubMed
      12. Thomas MF, Abdul-Wajid S, Panduro M, Babiarz JE, Rajaram M, Woodruff P, Lanier LL, Heissmeyer V, Ansel KM. Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviral function. Blood. 2012 Jul 5; 120(1):130-42.
        View in: PubMed
      13. Vijayanand P, Seumois G, Simpson LJ, Abdul-Wajid S, Baumjohann D, Panduro M, Huang X, Interlandi J, Djuretic IM, Brown DR, Sharpe AH, Rao A, Ansel KM. Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V. Immunity. 2012 Feb 24; 36(2):175-87.
        View in: PubMed
      14. Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M, Blelloch R, Ansel KM. MicroRNA-29 regulates T-box transcription factors and interferon-? production in helper T cells. Immunity. 2011 Aug 26; 35(2):169-81.
        View in: PubMed
      15. Baumjohann D, Okada T, Ansel KM. Cutting Edge: Distinct waves of BCL6 expression during T follicular helper cell development. J Immunol. 2011 Sep 1; 187(5):2089-92.
        View in: PubMed
      16. Sofi MH, Qiao Y, Ansel KM, Kubo M, Chang CH. Induction and maintenance of IL-4 expression are regulated differently by the 3' enhancer in CD4 T cells. J Immunol. 2011 Mar 1; 186(5):2792-9.
        View in: PubMed
      17. Parameswaran P, Sklan E, Wilkins C, Burgon T, Samuel MA, Lu R, Ansel KM, Heissmeyer V, Einav S, Jackson W, Doukas T, Paranjape S, Polacek C, dos Santos FB, Jalili R, Babrzadeh F, Gharizadeh B, Grimm D, Kay M, Koike S, Sarnow P, Ronaghi M, Ding SW, Harris E, Chow M, Diamond MS, Kirkegaard K, Glenn JS, Fire AZ. Six RNA viruses and forty-one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems. PLoS Pathog. 2010 Feb; 6(2):e1000764.
        View in: PubMed
      18. Thomas MF, Ansel KM. Construction of small RNA cDNA libraries for deep sequencing. Methods Mol Biol. 2010; 667:93-111.
        View in: PubMed
      19. Ansel KM, Pastor WA, Rath N, Lapan AD, Glasmacher E, Wolf C, Smith LC, Papadopoulou N, Lamperti ED, Tahiliani M, Ellwart JW, Shi Y, Kremmer E, Rao A, Heissmeyer V. Mouse Eri1 interacts with the ribosome and catalyzes 5.8S rRNA processing. Nat Struct Mol Biol. 2008 May; 15(5):523-30.
        View in: PubMed
      20. Haynes NM, Allen CD, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J Immunol. 2007 Oct 15; 179(8):5099-108.
        View in: PubMed
      21. Carvalho LD, Teixeira LK, Carrossini N, Caldeira AT, Ansel KM, Rao A, Viola JP. The NFAT1 transcription factor is a repressor of cyclin A2 gene expression. Cell Cycle. 2007 Jul 15; 6(14):1789-95.
        View in: PubMed
      22. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A, Frendewey D, Valenzuela D, Kutok JL, Schmidt-Supprian M, Rajewsky N, Yancopoulos G, Rao A, Rajewsky K. Regulation of the germinal center response by microRNA-155. Science. 2007 Apr 27; 316(5824):604-8.
        View in: PubMed
      23. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol. 2007 Feb; 8(2):145-53.
        View in: PubMed
      24. Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol. 2006; 24:607-56.
        View in: PubMed
      25. Monticelli S, Ansel KM, Xiao C, Socci ND, Krichevsky AM, Thai TH, Rajewsky N, Marks DS, Sander C, Rajewsky K, Rao A, Kosik KS. MicroRNA profiling of the murine hematopoietic system. Genome Biol. 2005; 6(8):R71.
        View in: PubMed
      26. Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, Rajewsky K. Aberrant T cell differentiation in the absence of Dicer. J Exp Med. 2005 Jul 18; 202(2):261-9.
        View in: PubMed
      27. Heissmeyer V, Ansel KM, Rao A. A plague of autoantibodies. Nat Immunol. 2005 Jul; 6(7):642-4.
        View in: PubMed
      28. Kabashima K, Banks TA, Ansel KM, Lu TT, Ware CF, Cyster JG. Intrinsic lymphotoxin-beta receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity. 2005 Apr; 22(4):439-50.
        View in: PubMed
      29. Monticelli S, Ansel KM, Lee DU, Rao A. Regulation of gene expression in mast cells: micro-rNA expression and chromatin structural analysis of cytokine genes. Novartis Found Symp. 2005; 271:179-87; discussion 187-90, 198-9.
        View in: PubMed
      30. Ansel KM, Greenwald RJ, Agarwal S, Bassing CH, Monticelli S, Interlandi J, Djuretic IM, Lee DU, Sharpe AH, Alt FW, Rao A. Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity. Nat Immunol. 2004 Dec; 5(12):1251-9.
        View in: PubMed
      31. Nardone J, Lee DU, Ansel KM, Rao A. Bioinformatics for the 'bench biologist': how to find regulatory regions in genomic DNA. Nat Immunol. 2004 Aug; 5(8):768-74.
        View in: PubMed
      32. Allen CD, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N, Cyster JG. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol. 2004 Sep; 5(9):943-52.
        View in: PubMed
      33. Ansel KM, Lee DU, Rao A. An epigenetic view of helper T cell differentiation. Nat Immunol. 2003 Jul; 4(7):616-23.
        View in: PubMed
      34. Luther SA, Ansel KM, Cyster JG. Overlapping roles of CXCL13, interleukin 7 receptor alpha, and CCR7 ligands in lymph node development. J Exp Med. 2003 May 5; 197(9):1191-8.
        View in: PubMed
      35. Ansel KM, Harris RB, Cyster JG. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity. 2002 Jan; 16(1):67-76.
        View in: PubMed
      36. Cyster JG, Ansel KM, Ngo VN, Hargreaves DC, Lu TT. Traffic patterns of B cells and plasma cells. Adv Exp Med Biol. 2002; 512:35-41.
        View in: PubMed
      37. Ansel KM, Cyster JG. Chemokines in lymphopoiesis and lymphoid organ development. Curr Opin Immunol. 2001 Apr; 13(2):172-9.
        View in: PubMed
      38. Cyster JG, Ansel KM, Reif K, Ekland EH, Hyman PL, Tang HL, Luther SA, Ngo VN. Follicular stromal cells and lymphocyte homing to follicles. Immunol Rev. 2000 Aug; 176:181-93.
        View in: PubMed
      39. Ansel KM, Ngo VN, Hyman PL, Luther SA, Förster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000 Jul 20; 406(6793):309-14.
        View in: PubMed
      40. Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J Exp Med. 1999 Oct 18; 190(8):1123-34.
        View in: PubMed
      41. Cyster JG, Ngo VN, Ekland EH, Gunn MD, Sedgwick JD, Ansel KM. Chemokines and B-cell homing to follicles. Curr Top Microbiol Immunol. 1999; 246:87-92; discussion 93.
        View in: PubMed
      42. Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature. 1998 Feb 19; 391(6669):799-803.
        View in: PubMed
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