Human and mouse ABCA1 comparative sequencing and transgenesis studies revealing novel regulatory sequences

The expression of ABCA1, a major participant in apolipoprotein-mediated cho lesterol efflux, is regulated by a variety of factors, including intracellu lar cholesterol concentration. To identify sequences involved in its regula tion, we sequenced and compared approximately 200 kb of mouse and human DNA containing the ABCA1 gene. Furthermore, expression of the human gene conta ining different 5 ' ends was examined in transgenic mice. Sequence comparis on revealed multiple conserved noncoding sequences. The two most highly con served noncoding elements (CNS1, 88% identity over 498 bp; CNS2, 81% identi ty over 214 bp) were also highly conserved in other organisms. Mice contain ing the human ABCA1 gene, 70 kb of upstream DNA, and 35 kb of downstream DN A expressed the transgene similarly to endogenous Abca1, A second transgene beginning 3 ' to exon 1 was expressed only in liver, providing strong evid ence of an unsuspected liver-specific promoter. The identified conserved no ncoding sequences invite further investigation to elucidate ABCA1 regulatio n. (C) 2001 Academic Press.