Regulation of gene expression in T and B cells

(a) My lab pioneered the field of epigenetic regulation of T cell responses. When we started our studies, the molecular basis for differentiation of naïve T cells into specific cytokine-producing T cell subsets (e.g. Th1 and Th2 cells) upon antigen and cytokine stimulation was entirely unclear. We were the first to show that T cell differentiation is accompanied by structural changes in chromatin that could be probed by changes in accessibility to DNase I, and that T cell differentiation results in selective chromatin changes in cytokine genes, at the level of histone modifications as well as accessibility of genomic regions to NFAT1 [13, 14]. (b) We were one of the first to probe the functions of selected regulatory DNA elements that become accessible during T cell differentiation by targeted disruption in the genome of mice [14]; also see PMID 12150890, 17195845). The work in (a) and (b) opened a new field of study on the epigenetic regulation of T cell differentiation that is being pursued to this day. (c) Through RNAi screening in mammalian cells, we were the first to discover hnRNPLL as the splicing regulator that controls activation-induced alternative splicing of the gene encoding the transmembrane phosphatase, CD45, and other genes in activated T cells [15] (also see PMID 22991471, 22326582, 25825742). Reviews on this subject from our lab: PMID: 12830136, 16551261.   13. Agarwal S, Rao A.  Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 1998; 9: 765-775; 14. Agarwal S, Avni O, Rao A. Cell-type-restricted binding of the transcription factor NFAT1 to a distal IL-4 enhancer in vivo. Immunity 2000; 12: 643-652. 15. 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.  Nature Immunol 2004; 5: 1251-1259 16. Oberdoerffer S, Moita LF, Neems DS, Freitas RA, Hacohen N, Rao A.  Regulation of CD45 alternative splicing by the heterogeneous ribonucleoprotein, HnRNP LL. Science 2008; 321: 686-691. PMC2791692