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J. Biol. Chem., Vol. 277, Issue 31, 27593-27605, August 2, 2002
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From the Department of Surgery, University of Pennsylvania Medical
System, Philadelphia, Pennsylvania 19104
The mammalian skeletal myosin heavy
chain locus is composed of a six-membered family of tandemly linked
genes whose complex regulation plays a central role in striated muscle
development and diversification. We have used publicly available
genomic DNA sequences to provide a theoretical foundation for an
experimental analysis of transcriptional regulation among the six
promoters at this locus. After reconstruction of annotated drafts of
the human and murine loci from fragmented DNA sequences, phylogenetic footprint analysis of each of the six promoters using standard and
Bayesian alignment algorithms revealed unexpected patterns of DNA
sequence conservation among orthologous and paralogous gene pairs. The
conserved domains within 2.0 kilobases of each transcriptional start
site are rich in putative muscle-specific transcription factor binding
sites. Experiments based on plasmid transfection in vitro
and electroporation in vivo validated several predictions
of the bioinformatic analysis, yielding a picture of synergistic
interaction between proximal and distal promoter elements in
controlling developmental stage-specific gene activation. Of particular
interest for future studies of heterologous gene expression is a
650-base pair construct containing modules from the proximal and distal
human embryonic myosin heavy chain promoter that drives extraordinarily
powerful transcription during muscle differentiation in
vitro.
Modular Organization of Phylogenetically Conserved Domains
Controlling Developmental Regulation of the Human Skeletal Myosin Heavy
Chain Gene Family*
,
*
This work was supported in part by grants (to H. S.) from
the Association Française contre les Myopathies (AFM), the
Muscular Dystrophy Association of America, NIAMS (National Institutes
of Health (NIH)), NINDS (NIH), and the Department of Veterans
Affairs.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
A postdoctoral fellow of the AFM.
§
To whom all correspondence should be addressed: Rm. 608, Biomedical
Research Bldg. II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160. Tel.: 215-898-1432; Fax: 215-573-8606; E-mail: hstedman@mail.med.upenn.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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