Nucleic Acids Research, Vol 25, Issue 8 1618-1625, Copyright © 1997 by Oxford University Press
HJ Klamut, LO Bosnoyan-Collins, RG Worton and PN Ray
In previous studies we have described a 5.0 kb Hin dIII fragment downstream
of muscle exon 1 that exhibits properties consistent with a muscle-specific
transcriptional enhancer. The goal of this study has been to identify the
sequence elements responsible for muscle-specific enhancer activity.
Functional studies indicated that this enhancer is active in pre- and
post-differentiated H9C2(2-1) myoblasts but functions poorly in L6 and
C2C12 myotubes. The core enhancer region was delimited to a 195 bp Spe I-
Acc I fragment and sequence analysis identified three MEF-1/E box and two
MEF-2/AT-rich motifs as potential muscle-specific regulatory domains. EMSA
competition and DNase footprinting indicated that sequences within a 30 bp
region containing single adjoining MEF-1/E box and MEF-2/AT-rich motifs are
target binding sites for trans -acting factors expressed in H9C2(2-1)
myotubes but not in L6 or C2C12 myotubes. Site-specific mutations within
these motifs resulted in a significant reduction in enhancer activity in
H9C2(2-1) myotubes. These results suggest that the mechanisms governing DMD
gene expression in muscle are similar to those identified in other
muscle-specific genes. However, the myogenic profile of enhancer activity
and trans -acting factor binding suggests a more specialized role for this
enhancer that is consistent with its potential involvement in dystrophin
gene regulation in cardiac muscle.
ARTICLES
A muscle-specific enhancer within intron 1 of the human dystrophin gene is functionally dependent on single MEF-1/E box and MEF-2/AT-rich sequence motifs
Division of Experimental Therapeutics, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. hklamut@oci.utoronto.ca
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