Study Of The Regulation Of Clustered Genes Expression

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 50 kb.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. LCR(Locus Control Region), containing four erythroid-specific hypersensitive sites and one non-erythroid-specific hypersensitive site and located 6-20kb upstream of the ε-globin gene, is generally acknowledged to be necessary for the high level expression of globin genes in erythroid tissues. In addition, a series of hypersensitive sites (Positive Control Element, PCE)located at the upstream of ζ-globin gene, are somewhat like LCR to regulate the a-like globin gene expression.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. As a new developmental vector system, bacterial artificial chromosome(BAC) based on the F factor of E.Coli can carry the foreign fragment more than 300kb and has several advantages, such as...