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We have ligated two cosmids through an oligonucleotide linker to produce a single fragment spanning 70 kb of the human alpha-globin cluster, in which the alpha-like globin genes (zeta 2, alpha 2 and alpha 1), their regulatory element (HS-40) and erythroid-specific DNase I hypersensitive sites accurately retain their normal genomic organization. The zeta (embryonic) and alpha (embryonic, fetal and adult) globin genes were expressed in all 17 transgenic embryos. Similarly, all fetal and adult mice from seven transgenic lines that contained one or more copies of the fragment, produced up to 66% of the level of endogenous mouse alpha-globin mRNA. However, as for smaller constructs containing these elements, human alpha-globin expression was not copy number dependent and decreased by 1.5-9.0 fold during development. These findings suggest that either it is not possible to obtain full regulation of human alpha-globin expression in transgenic mice or, more likely, that additional alpha-globin regulatory elements lie beyond the 70 kb segment of DNA analysed.

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

1994

Volume

22

Pages

4139 - 4147

Keywords

Animal Base Sequence Chromatin/chemistry Cosmids DNA/chemistry/*metabolism Deoxyribonuclease EcoRI Gene Expression Gene Expression Regulation Globins/*genetics Human Mice Mice, Inbred CBA Mice, Transgenic Molecular Sequence Data RNA, Messenger/metabolism *Regulatory Sequences, Nucleic Acid Support, Non-U.S. Gov't