Post-transcriptional regulation of thyroid hormone receptor expression by cis-acting sequences and a naturally occurring antisense RNA

Thyroid hormone (T-3) coordinates growth, differentiation, and metabolism by binding to nuclear thyroid hormone receptors (TRs), The TR alpha gene encodes T-3-activated TR alpha 1 (NR1Ala) as well as an antagonistic, non-T-3-binding alternatively spliced product, TR alpha 2 (NR1Alb). Thus, the TR alpha 1/TR alpha 2 ratio is a critical determinant of T-3 action. However, the mechanisms underlying this post-transcriptional regulation are unknown. We have identified a non-consensus, TR alpha 2-specific 5' splice site and conserved intronic sequences as key determinants of TR alpha mRNA processing. In addition to these cis-acting elements, a novel regulatory feature is the orphan receptor RevErbA alpha (NR1D1) gene, which is transcribed from the opposite direction at the same locus and overlaps the TR alpha 2 coding region. RevErbA alpha gene expression correlates with a high TR alpha 1/TR alpha 2 ratio in a number of tissues. Here we demonstrate that coexpression of RevErbA alpha and TR alpha regulates the TR alpha 1/TR alpha 2 ratio in intact cells. Thus, both cis- and trans-regulatory mechanisms contribute to cell-specific post-transcriptional regulation of TR gene expression and T-3 action.