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.