Regulation of the human α globin gene cluster in transgenic mice

Our understanding of ɑ and ß globin gene regulation has been advanced by the development of transgenic mouse technology. Major regulatory elements of both gene clusters have been identified. Extensive studies have shown that the genes, although co-ordinately expressed, differ in their regulation. Transgenic mice containing the ß locus control region (ßLCR) and the ß globin genes produce high level, developmentally regulated, copy number dependent expression of the genes. High level a globin gene expression can also be achieved in mice containing the α globin regulatory element, HS-40 and the α genes. However, expression levels are lower than the endogenous mouse α genes, are developmentally unstable and are copy number independent, implying that further regulatory sequences are necessary for full regulation of the cluster. The aim of this project was to identify potentially important regions in the a globin gene cluster. Mice, transgenic for a 145kb DMA fragment spanning the cluster showed higher expression levels in adults than in those previously studied. Although expression levels were developmentally stable and correlated with copy number, they did not reach those reported for ßLCRɑ constructs. A ßLCRɑ construct was examined. The results suggested that there were still unidentified regulatory elements to be found. A natural deletion which down regulated an intact α gene in vivo provided an indication as to where some of these sequences may lie. Analysis of the deleted fragment in transgenic mice implied that it might act to block the negative regulatory influence of an Alu dense region lying downstream, and hence, may have identified the 3’ end of a putative a globin domain'