Co-integration of beta-lactoglobulin/human serum albumin hybrid genes with the entire beta-lactoglobulin gene or the matrix attachment region element: repression of human serum albumin and beta-lactoglobulin expression in the mammary gland and dual regulation of the transgenes.

The effect of co-integration of the entire beta-lactoglobulin (BLG) gene or matrix attachment region (MAR) sequences on the expression of various BLG/ human serum albumin (HSA) gene constructs was tested in transgenic mice. These former sequences were chosen because of their reported ability to insulate transgenes from the neighboring host genomic DNA sequences and/or to provide a more permissive transcriptional environment. When introduced alone, a cDNA-based BLG/HSA construct was expressed in 60% of transgenic strains and HSA was secreted at levels up to 0.3 mg/ml into the milk. Upon co-integration with either the entire BLG gene or MAR element, HSA RNA and protein expression were completely abrogated. While the co-integrated BLG gene suppressed the proportion of expresser strains carrying cDNA as well as genomic BLG/HSA constructs, the MAR element only exerted its negative effect on the cDNA-based BLG/HSA construct. In transgenics expressing both HSA and BLG, the tissue specificity and developmental patterns of BLG expression were altered and resembled the less stringent pattern of the BLG/HSA expression. These results demonstrate that rescue of transgene expression through co-integration with BLG or MAR sequences do not apply universally.