K. Mark Ansel, Ph.D.
Associate Professor, Department of Microbiology & Immunology
Sandler Asthma Basic Research Center of UCSF
513 Parnassus Avenue
UCSF Box 0414, HSE-201H
San Francisco, CA 94143
Mark Ansel is an Associate Professor in the Department of Microbiology & Immunology. He completed a B.S. in biochemistry at Virginia Tech, a Ph.D. in Biomedical Sciences at UCSF, and postdoctoral training at the Immune Disease Institute at Harvard Medical School. His laboratory in the Sandler Asthma Basic Research Center focuses on the regulation of gene expression in the immune system.
MicroRNAs (miRNA), 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 gene expression analyses in cells from human clinical samples 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 RNAbinding 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 posttranscriptional regulation of gene expression by miRNAs and RNA binding proteins. 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.
- To determine how the expression and function of miRNAs contributes to the pathogenic properties of T cells in human asthma.
- To characterize the function of individual miRNAs that regulate T cell differentiation and immune effector functions.
- To define the molecular mechanisms that control miRNA homeostasis, and determine how the miRNA repertoire is so dramatically remodeled during T cell activation.
- Ramstein J, Broos CE, Simpson LJ, Ansel KM, Sun SA, Ho ME, Woodruff PG, Bhakta NR, Christian L, Nguyen CP, Antalek BJ, Benn BS, Hendriks RW, van den Blink B, Kool M, Koth LL. Interferon-gamma-producing Th17.1 Cells are Increased in Sarcoidosis and More Prevalent Than Th1 Cells. Am J Respir Crit Care Med. (2015) Dec 9.
- Patton JG, Franklin JL, Weaver AM, Vickers K, Zhang B, Coffey RJ, Ansel KM, Blelloch R, Goga A, Huang B, L'Etoille N, Raffai RL, Lai CP, Krichevsky AM, Mateescu B, Greiner VJ, Hunter C, Voinnet O, McManus MT. Biogenesis, delivery, and function of extracellular RNA. J Extracell Vesicles. (2015); 4:27494
- Pua HH, Ansel KM. MicroRNA regulation of allergic inflammation and asthma. Curr Opin Immunol. (2015) Oct; 36:101-8.
- Schaffert SA, Loh C, Wang S, Arnold CP, Axtell RC, Newell EW, Nolan G, Ansel KM, Davis MM, Steinman L, Chen CZ. mir-181a-1/b-1 Modulates Tolerance through Opposing Activities in Selection and Peripheral T Cell Function. J Immunol. (2015) Aug 15; 195(4): 1470-9.
- Simpson LJ, Ansel KM. MicroRNA regulation of lymphocyte tolerance and autoimmunity. J Clin Invest. (2015) Jun 1; 125(6): 2242-9.
- Warth SC, Hoefig KP, Hiekel A, Schallenberg S, Jovanovic K, Klein L, Kretschmer K, Ansel KM, Heissmeyer V. Induced miR-99a expression represses Mtor cooperatively Sandler Asthma Basic REsearch Center SABRE Investigators with miR-150 to promote regulatory T-cell differentiation. EMBO J. (2015) May 5; 34(9): 1195-213
- Simpson LJ, Patel S, Bhakta NR, Choy DF, Brightbill HD, Ren X, Wang Y, Pua HH, Baumjohann D, Montoya M, Panduro M, Remedios KA, Huang X, Fahy JV, Arron JR, Woodruff PG, and Ansel KM. A miRNA upregulated in asthma airway T cells promotes TH2 cytokine production. Nat Immunol 15:1162-70 (2014)
- Seumois G, Chavez L, Gerasimova A, Lienhard M, Omran N, Kalinke L, Vedanayagam M, Ganesan AP, Chawla A, Djukanović R, Ansel KM, Peters B, Rao A, Vijayanand P. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility. Nat Immunol 15:777-88 (2014)
- Baumjohann D and Ansel KM. MicroRNA regulation of T cell differentiation and plasticity. Nat Rev. Immunol. 13:666-78 (2013)
- Baumjohann D, Clingan JM, de Kouchkovsky D, Bannard O, Bluestone JA, Matloubian M, Ansel KM*, Jeker LT*. The microRNA cluster miR-17~92 is essential for follicular helper T cell differentiation. Nat Immunol. 14:840-8 (2013) (*co-corresponding authors)
- Ansel KM. RNA regulation in the immune system. Immunol Rev. 253:5-11 (2013)
- Bronevetsky YB and Ansel KM. Regulation of miRNA biogenesis and turnover in the immune system. Immunol Rev. 253:304-16 (2013)
- Bronevetsky Y, Villarino AV, Eisley C, Barbeau R, Barczak A, 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. 210:417-32 (2013)
- 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. 1:70-89 (2012)
- 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. 186:965-74 (2012)
- 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 anti-viral function. Blood. 120:130-42 (2012)
- 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 36:175-87 (2012)
- Baumjohann D, Okada T, Ansel KM. Cutting Edge: Distinct Waves of BCL6 Expression during T Follicular Helper Cell Development. J Immunol.187: 2089-92 (2011)
- 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-γ Production in Helper T Cells. Immunity 35:169-81 (2011)