Human Molecular Genetics, Vol 5, 1599-1606, Copyright © 1996 by Oxford University Press
HJ Klamut, LO Bosnoyan-Collins, RG Worton, PN Ray and HL Davis
The 14 kb muscle isoform of the Duchenne muscular dystrophy (DMD) gene is
expressed primarily in skeletal and cardiac muscle. Transcription of the
muscle isoform is induced as myoblasts differentiate into multinucleated
myotubes and transcript levels are increased a further 10-fold in mature
skeletal muscle. In previous studies we have demonstrated that the core
muscle promoter of the human DMD gene contains sequences that regulate the
induction of DMD gene expression with myoblast differentiation. However,
direct injection studies have indicated that the activity of the core
muscle promoter in mature skeletal muscle is 30-fold lower than in immature
myotubes. This discrepancy between endogenous transcript levels and core
promoter activity suggested that additional transcriptional elements are
involved in the regulation of DMD gene expression in muscle. In this report
we present evidence for the existence of a muscle-specific enhancer within
intron 1 of the human DMD gene. Functional analysis of Hindill fragments
from within a 36 kb region surrounding muscle exon 1 of the human DMD gene
resulted in the identification of a 5.0 kb fragment within muscle intron 1
that consistently provided high levels of reporter gene expression in both
immature and mature skeletal muscle. Sequences within this 5 kb fragment
were shown to be functionally independent of position and orientation and
to be inactive in fibroblasts, properties that are consistent with the
definition of a muscle-specific enhancer. Although this enhancer provided a
30-fold increase in transcription from a SV40 viral promoter in mature
skeletal muscle, only a 3-fold increase was observed from the DMD core
muscle promoter. Intron 1 enhancer activity alone is therefore insufficient
to account for the discrepancy between endogenous transcript levels and
core muscle promoter activity in immature and mature skeletal muscle and
points to the existence of additional enhancer elements in other regions of
the DMD gene. This report provides the first evidence for the involvement
of a transcriptional enhancer in DMD gene regulation in muscle and impacts
on our understanding of the functional consequences of mutations at the
5'-end of gene. In this regard, deletions in this region in X-linked
dilated cardiomyopathy patients provides indirect evidence for a role for
this enhancer in regulating DMD gene expression in cardiac muscle.
ARTICLES
Identification of a transcriptional enhancer within muscle intron 1 of the human dystrophin gene
Department of Medical Biophysics, University of Toronto, Ontario, Canada.
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