Duplicated downstream enhancers control expression of the human apolipoprotein E gene in macrophages and adipose tissue

Two distal enhancers that specify apolipoprotein (apo) E gene expression in isolated macrophages and adipose tissue were identified in transgenic mice that were generated with constructs of the human apoE/C-I/C-I'/C-IV/C-II g ene cluster. One of these enhancers, multienhancer 1, consists of a 620-nuc leotide sequence located 3.3 kilobases (kb) downstream of the apoE gene. Th e second enhancer, multienhancer 2, is a 619-nucleotide sequence located 15 .9 kb downstream of the apoE gene and 5.9 kb downstream of the apoC-I gene. The two enhancers are 95% identical in sequence, and they are likely to ha ve arisen as a consequence of the gene duplication event that yielded the a poC-I gene and the apoC-I' pseudogene. Both enhancer sequences appear to ha ve equivalent activity in directing apoE gene expression in peritoneal macr ophages and in adipocytes, suggesting that their activity in specific cell types may be determined by common regulatory elements.