Transgenic Mice Research Based On BAC Containing The Entire Human β-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 arranged in the order of 5'- ζ -ψζ -ψα-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 75 kb. 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 α-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. Five DNasel-hypersensitive sites (5'HS1-5), located 6-20 kb upstream of the ε -globin gene, were termed the locus control region (LCR). LCR is generally acknowledged to be necessary for the high level expression of globin genes in erythroid tissues. In addition, another developmentally stable DNasel HS site and some regulatory elements are located in regions downstream of the β -globin gene. Thus, sequences spanning a region of over 100 kb have been included in the control of the human β -globin genes.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...