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Gene Regulation and Molecular Immunology Laboratory
Dr. Nikos Yannoutsos
Group members: Georgia Vogl
Research Interests
While the information encoded in the DNA of the genes is ultimately the blueprint of an organism, the regulation of the expression of this information is of critical importance for the realization of the blueprint. This regulation depends on DNA sequences such as promoters, enhancers and locus control regions (LCRs) which surround the genes in the non-transcribed and non-translated areas of the genome. However, genetic information is also regulated by "epigenetic" information, i.e. by inherited states of gene regulation that lies outside of the DNA of a gene and the dictates of its specific genetic structure. Such epigenetic mechanisms include DNA methylation, histone modifications and RNA interference (RNAi). Recent research indicates that the mechanisms are interrelated and affect the packaging of the genes into chromatin. The dynamic change of the three-dimensional architecture of chromatin is a modulator of the accessibility of the genes to the transcriptional apparatus and to specific regulatory mechanisms in different tissues and developmental stages and is, itself, modulated by them.
The immune system is as complex as the nervous system. It is characterized by communication among its component cells as well as between them and the environment. This communication is based on the biochemical specificity of the molecules carried by individual cells, the B or T cell receptors (BCR and TCR). V(D)J recombination creates BCRs and TCRs by looping out and eliminating large chromosomal segments that separate the regions which encode the variable (V), the Diversity (D) and the Joining (J) parts of these receptors. The process occurs in four subpopulations of lymphocyte precursors, namely in pro- and pre-B cells in the bone marrow and in double negative (DN) and double positive (DP) T cells in the thymus.
The enzymes that are required for this process are the products of the Recombination Activating Genes RAG1 and RAG2.
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The movie shows successive areas of the mouse Rag locus stained red and green within a DAPI stained interphase nucleus of a DP thymocyte. |
The two genes are closely linked and conserved in evolution. Transcription of the genes is co-ordinately up regulated in pro-B and DN T cells, down regulated as the cells proliferate and up regulated again as the cells become pre-B and DP T. Finally, the genes are down regulated again as the cells mature into the B and T cells of the immune system. Several elements in cis, in the areas of the DNA surrounding the genes, act in concert to effect this regulation by silencing and anti-silencing mechanisms that are still not well understood. Our current research (ref. 1,2) indicates that these mechanisms include secondary, epigenetic, regulation of the Rag locus over at least 100 kilobases.
We are interested in clarifying the cis and trans regulation of this locus including genetic and epigenetic mechanisms.
1. Yannoutsos, N. et al. A cis element in the recombination activating gene locus regulates gene expression by counteracting a distant silencer. Nat Immunol 5, 443-50 (2004).
2. Yannoutsos, N. et al. The Role of Recombination Activating Gene (RAG) Reinduction in Thymocyte Development In Vivo. J. Exp. Med. 194, 471-480 (2001).