Epigenetic regulation in the immune system

At the heart of our immunity to disease lies the ability of the immune system to recreate a great variety of genes from germline chromosomal segments. This rearrangement of the genome is mediated by the product of two genes called recombination activating genes 1 and 2 (RAG1 and RAG2). Rearrangement of the genome is a dangerous process for an organism and is, therefore, strictly regulated at all levels of cellular activity, starting with the regulation of expression of the RAGs themselves. The subject of this application is the study of the regulation of the transcription of these genes during lymphocyte development. The two genes are closely linked and conserved in evolution. 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. Current research indicates that these mechanisms include secondary, epigenetic, regulation of the chromatin architecture of the locus of these genes over a large area. This may also be partly dependent on the action of regulatory RNA molecules, a general mechanism of gene regulation that has been a topic of intense scientific interest in recent years. Insight into the mechanisms involved in the complex regulation of the RAG locus will contribute to the study of gene regulation in general. This research is basic research aimed at improving our understanding of the immune system and our capacity to fight disease.

At the heart of our immunity to disease lies the ability of the immune system to recreate a great variety of genes from germline chromosomal segments. This rearrangement of the genome is mediated by the product of two genes called recombination activating genes 1 and 2 (RAG1 and RAG2). Rearrangement of the genome is a dangerous process for an organism and is, therefore, strictly regulated at all levels of cellular activity, starting with the regulation of expression of the RAGs themselves. The subject of this application is the study of the regulation of the transcription of these genes during lymphocyte development. The two genes are closely linked and conserved in evolution. 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. Current research indicates that these mechanisms include secondary, epigenetic, regulation of the chromatin architecture of the locus of these genes over a large area. This may also be partly dependent on the action of regulatory RNA molecules, a general mechanism of gene regulation that has been a topic of intense scientific interest in recent years. Insight into the mechanisms involved in the complex regulation of the RAG locus will contribute to the study of gene regulation in general. This research is basic research aimed at improving our understanding of the immune system and our capacity to fight disease.