© 1997 American Heart Association, Inc.
Articles |
Conserved Enhancer Elements in Human and Mouse Renin Genes Have Different Transcriptional Effects in As4.1 Cells
From the Cardiovascular Center (Y.Y., D.F.C.), Cornell University Medical College, New York, NY; the Department of Physiology (C.D.S.), University of Iowa College of Medicine, Iowa City; and the Department of Molecular Biology (C.A.J., K.W.G.), Roswell Park Cancer Institute, Buffalo, NY.
Correspondence to Daniel F. Catanzaro, PhD, Cardiovascular Center, Cornell University Medical College, 1300 York Ave, Room A863, New York, NY 10021. E-mail dfcatanz{at}mail.med.cornell.edu
Abstract Despite the strong conservation of proximal
5'-flanking DNA sequences, cell transfection and transgenic animal
studies have failed to provide a unifying hypothesis to explain the
expression of both mouse and human renin genes. Recently, sequences
contained in the mouse Ren-1C gene 5'-flanking
DNA (–2866 to –2625) were shown to contain an enhancer-like element
that stimulates Ren-1C promoter activity in
renin-expressing As4.1 cells 
80-fold. Earlier studies using
transgenic mice had suggested that this same region is required for the
cell-specific expression of mouse renin genes. Since existing human
renin genomic clones lack sequences homologous to the mouse renin
enhancer, we isolated several human P1 and P1 artificial chromosome
genomic clones that contain >80 kb spanning the human renin gene.
Analysis of these clones by Southern blot hybridization and
long-range polymerase chain reaction showed that they contain sequences
homologous to the mouse enhancer at 12 kb upstream of the
transcription start site. Mouse and human sequences were 59% identical
over a 650-bp region that contained the minimal enhancer from the mouse
Ren-1C gene. However, a 1-kb fragment containing
the entire human enhancer homology failed to stimulate human renin
promoter activity in transiently transfected As4.1 cells. Further
deletional analysis showed that a 220-bp region of the human
sequence highly conserved in the mouse Ren-1C
gene exhibited up to 47-fold transcriptional stimulation, although this
was lower than the maximal effect exhibited by the minimal mouse
enhancer (223-fold). Taken together, these observations suggest that
sequences surrounding the conserved enhancer core stimulate enhancer
activity in the mouse gene but suppress activity in the human gene. The
high transcriptional activity of the mouse enhancer may have evolved to
support the exceptionally high plasma renin concentrations found in
mice. However, the enhancer core and surrounding conserved sequences
may play an additional role in directing cell specificity.
Key Words: renin gene expression • enhancer • As4.1 cell
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