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 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 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 Ansel lab's primary experimental system is the differentiation of the central coordinators of adaptive immune responses -- helper T cells. Their distinct cellular identities (Th1, Th2, Th17, 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 have become very interested in the roles played by microRNAs (miRNAs). 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. One of the goals of our research is to determine which specific miRNAs regulate each of these T cell behaviors, and which protein coding mRNAs the miRNAs target to exert their effects. In addition, we learned that T cells rapidly reset their miRNA repertoire upon activation. 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.
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 9;36(2):175-87. February 9, 2012
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. 2011 Aug;35(2):169-181. August 3, 2011
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. July 29, 2011
Thomas MF, Ansel KM. Construction of small RNA cDNA libraries for deep sequencing. Methods Mol Biol. 2010;667:93-111. June 4, 2010
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. April 27, 2008
Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM. T-bet and Runx3 cooperate to activate Ifng and silence Il4 in Th1 cells. Nat. Immunol.8:145-53 (2007)
Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation and the IL4 locus. Annu. Rev. Immunol. 24:607-56 (2006)