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J. Biol. Chem., Vol. 281, Issue 50, 38330-38342, December 15, 2006

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Dynamics of Myosin Heavy Chain Gene Regulation in Slow Skeletal Muscle

ROLE OF NATURAL ANTISENSE RNA^*

Clay E. Pandorf, Fadia Haddad, Roland R. Roy, Anqi X. Qin, V. Reggie Edgerton^¶, and Kenneth M. Baldwin¹

From the Department of Physiology and Biophysics, University of California, Irvine, California 92697, the Brain Research Institute and ^¶Department of Physiological Sciences, University of California, Los Angeles, California 90095

The evolutionarily conserved order of the skeletal muscle myosin heavy chain (MHC) genes and their close tandem proximity on the same chromosome are intriguing and may be important for their coordinated regulation. We investigated type II MHC gene regulation in slow-type muscle fibers undergoing a slow to fast MHC transformation in response to inactivity, 7 days after spinal cord isolation (SI) in rats. We examined the transcriptional products of both the sense and antisense strands across the IIa-IIx-IIb MHC gene locus. A strand-specific reverse transcription (RT)-PCR approach was utilized to study the expression of the mRNA, the primary transcript (pre-mRNA), the antisense RNA overlapping the MHC genes, and both the intergenic sense and antisense RNAs. Results showed that the mRNA and pre-mRNA of each MHC had a similar response to SI, suggesting regulation of these genes at the transcriptional level. In addition, we detected previously unknown antisense strand transcription that produced natural antisense transcripts (NATs). RT-PCR mapping of the RNA products revealed that the antisense activity resulted in the formation of three major products: aII, xII, and bII NATs (antisense products of the IIa, IIx, and IIb genes, respectively). The aII NAT begins in the IIa-IIx intergenic region in close proximity to the IIx promoter, extends across the 27-kb IIa MHC gene, and continues to the IIa MHC gene promoter. The expression of the aII NAT was significantly up-regulated in muscles after SI, was negatively correlated with IIa MHC gene expression, and was positively correlated with IIx MHC gene expression. The exact role of the aII NAT is not clear; however, it is consistent with the inhibition of IIa MHC gene transcription. In conclusion, NATs may mediate cross-talk between adjacent genes, which may be essential to the coordinated regulation of the skeletal muscle MHC genes during dynamic phenotype shifts.

Received for publication, July 31, 2006 , and in revised form, September 29, 2006.

^* This research was supported by National Institutes of Health Grants AR30346 (to K. M. B.) and NS16333 (to V. R. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ872905 [GenBank] (IIa MHC), DQ872906 [GenBank] (IIx MHC), DQ872907 [GenBank] (IIb MHC).

¹ To whom correspondence should be addressed. Tel.: 949-824-7192; Fax: 949-824-8540; E-mail: kmbaldwi{at}uci.edu.

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