Transgenic Mice Research Based On BAC Containing The Entire Human α-Globin Gene Cluster

The human globin gene family consists of α - and β -globin gene clusters. The α-globin gene cluster locates on the short arm of chromosome 16 and is arranged in the order of 5'-ζ-ψζ-ψα2- ψα1-α2-α1-θ-3', spanning about 40kb; the β-globin gene cluster is on the short arm of chromosome 11 and in the order of 5'-ε -Gγ -Aγ-ψβ-δ -β-3' , spanning about 75kb. The DNA sequences of the two clusters have been determined.The expressions of globin genes are characterized by 1) sequential expression of individual gene in each cluster, 2)erythroid-specific and developmental stage-specific expression, 3) balance between a -like and β-like globin chains. The transcription of globin genes is regulated by the chromatin structure, methylation of globin genes and their flanking regions, local and distal cis-acting elements and cellular trans-acting factors.There are five DNaseI-hypersensitive sites (5' HS4,8, 10, 33 and 40), located 4-40 kb upstream of the ζ-globin gene. Although HS-40 is generally acknowledged to be necessary for the high level expression of α -like globin genes in erythroid tissues, the function of other HS sites are not thoroughly investigated.Studies of expression regulation of eukaryotic genes in transgenic mice permit not only the devices of experiments on molecular level but also the observation of the involvement of almost all the factors affecting gene expression and investigations of in vivo effect of gene regulations. Transgenic technique can be applied to set up transgenic models for human genetic diseases from which expression regulation of abnormal genes are demonstrated and many pre-clinical data for human gene therapy will be provided. The cosmid and yeast artificial chromosome (YAC) systems can be combined with transgenic technique to investigate the developmental regulation of large gene clusters. There are several limitations in the...