Evolutionary duplication of a hepatic control region in the human apolipoprotein E gene locus. Identification of a second region that confers high level and liver-specific expression of the human apolipoprotein E gene in transgenic mice.
We have identified a second hepatic control region (HCR-2) in the human apolipoprotein (apo) E gene locus that confers liver expression of the human apoE gene in transgenic mice. This HCR-2 sequence is located 27 kilobases downstream of the apoE gene and 10 kilobases downstream of the previously described liver-specific enhancer (HCR-1). Nucleotide sequence analysis of the HCR-2 region revealed a sequence that shares 85% identity to the functional 319-base pair domain of HCR-1. To test its activity, transgenic mice were prepared with a fusion construct containing a human apoE gene fragment, which is not normally expressed in the liver, ligated to a 632-base pair region containing the HCR-2 sequence. This construct resulted in high levels of liver-specific apoE transgene expression, indicating that HCR-2 can function as a hepatic enhancer and has an activity similar to that of HCR-1. Hence, these findings suggest that there are at least two hepatic control regions, HCR-1 and HCR-2, capable of controlling the liver expression of this human apolipoprotein gene locus.
Allan
C M
CM
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco 94141-9100, USA.
Walker
D
D
Taylor
J M
JM
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001483:Base Sequence; D005075:Biological Evolution; D003001:Cloning, Molecular; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D015894:Genome, Human; D015186:Hominidae / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D005810:Multigene Family; D009928:Organ Specificity; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D012689:Sequence Homology, Nucleic Acid
D001057:Apolipoproteins E; D012333:RNA, Messenger