Activity of the β-myosin heavy chain antisense promoter responds to diabetes and hypothyroidism

Authors:
  • AQAnqi X. Qin
    Anqi X. Qin
  • PBPaul W. Bodell
    Paul W. Bodell
  • KBKenneth M. Baldwin
    Kenneth M. Baldwin
  • FHFadia Haddad
    Fadia Haddad
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Abstract
Two genes encoding cardiac myosin heavy chain (MHC) isoforms, β and α, are arranged in tandem 4.5 kb apart. We examined pre-mRNA and mature mRNA levels of β and α genes in control, diabetic (streptozotocin), hypothyroid (propylthiouracil), and hyperthyroid rat hearts and analyzed the naturally occurring antisense (AS) β RNA species that starts in the middle of the 4.5-kb intergenic region and extends upstream to the β-gene promoter. The β and α genes are expressed antithetically in control, diabetic, hypothyroid, and hyperthyroid hearts. Expression of AS β-RNA was positively correlated with α-mRNA and negatively correlated with sense β mRNA. These results support the novel idea of common promoter-regulatory elements situated in the intergenic region that likely control transcription of both sense α and AS β genes and that AS β transcription negatively regulates β-MHC gene expression. To test whether an intergenic promoter drives transcription of AS β RNA, a 1340-bp sequence of the intergenic region was inserted into a luciferase plasmid in the 3′-to-5′ AS direction and was injected into rat ventricle. This promoter was activated in control heart and decreased greatly in response to propylthiouracil and streptozotocin and increased in hyperthyroid rats, similar in pattern to the endogenous AS β RNA. When a putative retinoic acid receptor (RAR) site (a known thyroid hormone receptor cofactor) in this promoter was mutated, the reporter activity was almost abolished in control, propylthiouracil, and streptozotocin hearts. We conclude that there is an intergenic promoter that is active in the AS direction and that the putative RAR element is a vital regulatory site.
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