Regulation of an antisense RNA with the transition of neonatal to IIb myosin heavy chain during postnatal development and hypothyroidism in rat skeletal muscle

Am J Physiol Regul Integr Comp Physiol. 2012 Apr;302(7):R854-67. doi: 10.1152/ajpregu.00591.2011. Epub 2012 Jan 18.

Abstract

Postnatal development of fast skeletal muscle is characterized by a transition in expression of myosin heavy chain (MHC) isoforms, from primarily neonatal MHC at birth to primarily IIb MHC in adults, in a tightly coordinated manner. These isoforms are encoded by distinct genes, which are separated by ∼17 kb on rat chromosome 10. The neonatal-to-IIb MHC transition is inhibited by a hypothyroid state. We examined RNA products [mRNA, pre-mRNA, and natural antisense transcript (NAT)] of developmental and adult-expressed MHC genes (embryonic, neonatal, I, IIa, IIx, and IIb) at 2, 10, 20, and 40 days after birth in normal and thyroid-deficient rat neonates treated with propylthiouracil. We found that a long noncoding antisense-oriented RNA transcript, termed bII NAT, is transcribed from a site within the IIb-Neo intergenic region and across most of the IIb MHC gene. NATs have previously been shown to mediate transcriptional repression of sense-oriented counterparts. The bII NAT is transcriptionally regulated during postnatal development and in response to hypothyroidism. Evidence for a regulatory mechanism is suggested by an inverse relationship between IIb MHC and bII NAT in normal and hypothyroid-treated muscle. Neonatal MHC transcription is coordinately expressed with bII NAT. A comparative phylogenetic analysis also suggests that bII NAT-mediated regulation has been a conserved trait of placental mammals for most of the eutherian evolutionary history. The evidence in support of the regulatory model implicates long noncoding antisense RNA as a mechanism to coordinate the transition between neonatal and IIb MHC during postnatal development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gene Expression Regulation, Developmental*
  • Hypothyroidism / chemically induced
  • Hypothyroidism / metabolism*
  • Muscle, Skeletal / growth & development*
  • Muscle, Skeletal / metabolism
  • Myosin Heavy Chains / genetics*
  • Nonmuscle Myosin Type IIB / genetics*
  • Propylthiouracil / adverse effects
  • RNA, Antisense / genetics
  • RNA, Antisense / metabolism*
  • Rats
  • Transcription, Genetic

Substances

  • RNA, Antisense
  • Propylthiouracil
  • Nonmuscle Myosin Type IIB
  • nonmuscle myosin type IIB heavy chain
  • Myosin Heavy Chains