Developmental-stage and cell-type specific activities of the mouse T cell receptor-alpha locus control region

The genomes of multicellular eukaryotes encode tens of thousands of genes, with but a small proportion of these being expressed in any given cell-type. An understanding of the mechanisms governing the spatial patterns and the developmental timing of gene expression is of particular interest to biologists and is a prerequisite for the development of effective forms of treatment of genetic disorders. The work presented here focuses on the regulation of the T cell-specifically expressed mouse T cell receptor alpha (TCRalpha) gene. The TCRalpha locus contains a powerful cis-acting transcriptional regulatory element known as a locus control region (LCR). An LCR is defined by its ability to confer upon linked reporter transgenes high-level, tissue-specific and copy number-dependent expression, independent of the site of chromosomal integration. The TCRalpha LCR is flanked in the genome by three differentially expressed genes.; It is of particular interest to determine the role of the LCR in the expression of the genes in its locus as well as understand the molecular basis for its powerful activity at ectopic sites. Transgenic mouse models have been employed here to investigate the functions of key LCR elements as well as activities of the LCR as a whole. These studies have lead to the identification of discrete sequences involved in regulating chromatin accessibility. This work has also produced evidence of the importance of LCR function during thymic development and, surprisingly suggests the involvement additional, as yet uncharacterized elements in the specification of peripheral patterns of gene expression in the locus. It will be important to identify the elements involved in the differential mechanisms of thymic and peripheral T cell gene regulation described here, and to determine the overall significance of these mechanisms to T cell biology.