294:H14-H15, 2008. First published 9 November 2007;
Am J Physiol Heart Circ Physiol
John G. Edwards
Cardiac MHC gene expression: more complexity and a
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Cardiac MHC gene expression: more complexity and a step forward
John G. Edwards
Department of Physiology, New York Medical College, Valhalla, New York
WITHIN CARDIAC MUSCLE, the myosin heavy chain (MHC) protein
is a major component of the contractile machinery. MHC
provides structural integrity, and its isoform is a major deter-
minant of contractile and functional properties of the myocar-
dium (1, 8). Cardiac MHC isoforms exist as homologous or
heterologous dimers, and a unique gene product encodes each.
At the genomic level, ?- and ?-MHC genes are organized in
tandem over a 60-kb region on human chromosome 14 (18). At
the protein level, the cardiac ?- and ?-MHC proteins have a
high degree (94%) of sequence identity, and divergence
only occurs in clusters of functionally important regions
such as the ATPase catalytic site (16). Although the human
heart expresses predominantly the ?-MHC protein, a small
but significant amount of ?-MHC is present. The proportion
of ?-MHC has been shown to decline in the failing human
heart, which is likely to contribute to a decline in cardiac
performance (14, 17).
Studies focusing on the thyroid hormone (3,5,3?-triiodothy-
ronine, T3) regulation of cardiac MHC transcription have
spanned more than two decades (13). Earlier efforts to eluci-
date the mechanisms for T3-induced changes in MHC tran-
scription have ranged from variable for the control of ?-MHC
transcription to less than satisfying for the control of ?-MHC
transcription (2, 4, 19). These studies and others examined
regulation of a single gene, whereby an activated T3receptor
binds to the “promoter region” of a gene to modify its tran-
scription. The levels of complexity were elevated by observa-
tions that T3-induced changes in MHC transcription were
modified by the participation of alternatively spliced T3recep-
tors and that T3 receptors were able to form homo- or het-
erodimers with other members of the steroid receptor family,
permitting many combinations that could influence cardiac
MHC transcription (10).
In their recent article in the American Journal of Physiology-
Heart and Circulatory Physiology, Haddad et al. (7a) argue for
a coordinated regulation that spans both gene products, view-
ing them as a single regulated entity. The authors have made
use of strand-specific reverse transcription of RNA to examine
both developmental and hormonally induced changes in car-
diac MHC gene transcription. Previously this group had dem-
onstrated the presence of an antisense ?-MHC transcript whose
expression was increased by both hypothyroidism and pressure
overload (6, 7). In their present study increases in the antisense
?-MHC transcript following birth or in response to increases in
T3inversely matched changes in ?-MHC mRNA levels. This
suggests an alternative to a T3 receptor-mediated interaction
within the promoter region of the ?-MHC gene, as a control-
ling function of ?-MHC expression. The antisense ?-MHC
RNA transcript originated from transcription initiated in the
intergenic (IG) region between the ?-MHC and ?-MHC coding
regions. The present report by Haddad et al. extends those
observations to show that transcription from the IG locus is
bidirectional and that in addition to the antisense ?-MHC
transcript being synthesized, a sense IG RNA transcript that
merges with the ?-MHC pre-mRNA is also present. The sense
IG RNA transcript is also sensitive to both thyroid state and
developmental stage. Phylogenetic analyses of the IG region
identified a highly conserved region of ?80% across five
species, located between the start sites that potentially may
serve as a promoter region for the two transcripts.
The mechanisms by which each of these novel transcripts
functions remain unclear. It has only recently been appreciated
that bidirectional transcription is prevalent in the mammalian
transcriptome, and its role and mechanisms remain to be
elucidated (11). It is not known whether the antisense ?-MHC
transcript acts by RNA interference or whether it serves to
modify transcriptional/translation processes by some other
means. Alternatively, it may be that the antisense ?-MHC
transcript is further processed to generate a microRNA. van
Rooij et al. (20) recently reported a microRNA transcript from
?-MHC intron 27. The miR-208 also participated in T3repres-
sion of ?-MHC expression, possibly through an interaction
with the THRAP1 protein. And it remains to be determined
whether the antisense ?-MHC transcript operates similarly.
The role of the sense IG transcript also remains unresolved.
Dennehey et al. (3) identified alternative transcription start
sites and alternative splicing for several striated muscle MHC
genes including the ?-MHC and ?-MHC genes. The alterna-
tive transcripts were localized only to the 5? untranslated
regions (UTR) and not the coding regions. Their findings are
significant since the presence of alternative 5?UTR could
directly impact on mRNA stability or translation initiation,
which is the rate-limiting step for translation. In the present
study of Haddad et al., the sense IG transcript and the mature
?-MHC-mRNA transcript appear equally sensitive to T3; how-
ever, developmentally they appear to move in different direc-
tions. Whether this is a mechanism of development or reflec-
tive of developmental processes also remains to be determined.
The authors’ argument for viewing the MHC genes as a
single regulated entity is timely. A great deal more is now
understood about the role of chromatin structure in transcrip-
tional regulation (15). Earlier studies demonstrated that the
cardiac MHC genes were DNase sensitive and that this sensi-
tivity could by altered by T3, suggesting a potential role for
chromatin remodeling (9). More recently, studies focusing on
histone acetylation have demonstrated a significant role for
chromatin remodeling in mediating the myocardial response to
cardiac overload (12). Thyroid hormone effects could be me-
diated by the thyroid-associated proteins (TRAPs), which are
known to interact with members of the transcriptional complex
and have intrinsic acetylation activity (5). The phylogenic
analyses of the intergenic MHC region as reported by Haddad
et al. (7a) identified an abundance of T3receptor (T3R)/retinoic
acid receptor (RAR/RXR) binding sites within the IG region
Address for reprint requests and other correspondence: J. G. Edwards, Dept.
of Physiology, New York Medical College, Valhalla, NY 10595 (e-mail:
Am J Physiol Heart Circ Physiol 294: H14–H15, 2008;
0363-6135/08 $8.00 Copyright © 2008 the American Physiological Societyhttp://www.ajpheart.org H14
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that could mediate T3-induced alterations but also serve as a Download full-text
focal point for the epigenetic regulation of the MHC genes.
At the genomic level, ?- and ?-MHC genes are organized in
tandem over a 60-kb region on human chromosome 14, while
the six skeletal MHC genes are found over a 600-kb span on
human chromosome 17 (21). Understanding the mechanisms
of transcriptional regulation of the cardiac genes not only will
increase our understanding of cardiac physiology but will
provide a conceptual basis for a more complete understanding
of transcriptional regulation of the skeletal MHC genes.
This work was supported in part by National Heart, Lung, and Blood
Institute Grant PO1-HL-43023 and the New York Medical College Research
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