Human and mouse ABCA1 comparative sequencing and transgenesis studies identify regulatory elements

Journal Article · Tue Aug 01 04:00:00 EDT 2000 · Circulation

OSTI ID:776631

Qiu, Yang ^[1]; Cavelier, L; Chiu, Sally; Rubin, Edward; Cheng, Jan-Fang

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1. LBNL Library

The expression of ABCA1, a major participant in apolipoprotein mediated cholesterol efflux is highly regulated by a variety of factors including intracellular cholesterol concentration. To analyze its genomic organization and identify those sequences involved in its regulation we sequenced and compared approximately 200 Kb of orthologous DNA from mice and humans containing the ABCA1 gene and significant flanking DNA. The comparison revealed a variety of mouse human conserved sequences including 50 conserved ABCA1 exons over 147Kb of human and 124Kb of mouse genomic DNA as well as multiple mouse human conserved noncoding sequences. Using as a criteria for identifying putative regulatory elements in non-coding sequence, human and mouse sequences that were &62;75% identical for over 120 bp were screened for resulting in the identification of 34 elements. The two most highly conserved human mouse noncoding elements (CNS1: 88% identity over 498 bp, CNS2: 81% identity over 214 bp)! were also highly conserved in the ABCA1 genes of rats, dogs, cows, rabbits and pigs. Two independent studies have demonstrated that the DNA segments containing CNS2 function in vitro as a sterol response promoter. Support for the inclusion of major ABCA1 regulatory elements in the human genomic sequence examined was the demonstration that mice containing a human BAC transgene containing sequences exclusively from the analyzed interval, expressed human ABCA1 in a tissue distribution mimicking expression of endogenous mouse ABC1. These studies using a comparative genomic approach has characterized the structure of the human and mouse ABCA1 genes and has helped identify sequences participating in its expression.

• Research Organization: Lawrence Berkeley National Lab., CA (US)
• Sponsoring Organization: USDOE Director, Office of Science (US)
• DOE Contract Number: AC03-76SF00098
• OSTI ID: 776631
• Report Number(s): LBNL--46640
• Journal Information: Circulation, Journal Name: Circulation Journal Issue: 18 Supplement Vol. 102; ISSN 0009-7322; ISSN CIRCAZ
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
APOLIPOPROTEINS
CHOLESTEROL
COWS
DNA
GENES
IN VITRO
MICE
RABBITS
STEROLS
TISSUE DISTRIBUTION