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EDITORIAL FOCUS
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 determinant of contractile and functional properties of the myocardium (1, 8). Cardiac MHC isoforms exist as homologous or heterologous dimers, and a unique gene product encodes each. At the genomic level, 
- and β-MHC genes are organized in tandem over a 60-kb region on human chromosome 14 (18). At the protein level, the cardiac - and β-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 β-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'-triiodothyronine, T3) regulation of cardiac MHC transcription have spanned more than two decades (13). Earlier efforts to elucidate the mechanisms for T3-induced changes in MHC transcription have ranged from variable for the control of -MHC transcription to less than satisfying for the control of β-MHC transcription (2, 4, 19). These studies and others examined regulation of a single gene, whereby an activated T3 receptor binds to the "promoter region" of a gene to modify its transcription. The levels of complexity were elevated by observations that T3-induced changes in MHC transcription were modified by the participation of alternatively spliced T3 receptors and that T3 receptors were able to form homo- or heterodimers 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, viewing 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 cardiac MHC gene transcription. Previously this group had demonstrated the presence of an antisense β-MHC transcript whose expression was increased by both hypothyroidism and pressure overload (6, 7). In their present study increases in the antisense β-MHC transcript following birth or in response to increases in T3 inversely matched changes in β-MHC mRNA levels. This suggests an alternative to a T3 receptor-mediated interaction within the promoter region of the β-MHC gene, as a controlling function of β-MHC expression. The antisense β-MHC RNA transcript originated from transcription initiated in the intergenic (IG) region between the -MHC and β-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 β-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 β-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 β-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 T3 repression of β-MHC expression, possibly through an interaction with the THRAP1 protein. And it remains to be determined whether the antisense β-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 β-MHC genes. The alternative 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; however, developmentally they appear to move in different directions. Whether this is a mechanism of development or reflective 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 transcriptional regulation (15). Earlier studies demonstrated that the cardiac MHC genes were DNase sensitive and that this sensitivity 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 mediated 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 T3 receptor (T3R)/retinoic acid receptor (RAR/RXR) binding sites within the IG region that could mediate T3-induced alterations but also serve as a focal point for the epigenetic regulation of the MHC genes.
At the genomic level, - and β-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.
GRANTS
This work was supported in part by National Heart, Lung, and Blood Institute Grant PO1-HL-43023 and the New York Medical College Research Endowment Fund.
FOOTNOTES
Address for reprint requests and other correspondence: J. G. Edwards, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (e-mail: j_edwards{at}nymc.edu)
REFERENCES
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