Post-transcriptional Regulation of Thyroid Hormone Receptor Expression by cis-Acting Sequences and a Naturally Occurring Antisense RNA

Abstract

Thyroid hormone (T(3)) coordinates growth, differentiation, and metabolism by binding to nuclear thyroid hormone receptors (TRs). The TRalpha gene encodes T(3)-activated TRalpha1 (NR1A1a) as well as an antagonistic, non-T(3)-binding alternatively spliced product, TRalpha2 (NR1A1b). Thus, the TRalpha1/TRalpha2 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, TRalpha2-specific 5' splice site and conserved intronic sequences as key determinants of TRalpha mRNA processing. In addition to these cis-acting elements, a novel regulatory feature is the orphan receptor RevErbAalpha (NR1D1) gene, which is transcribed from the opposite direction at the same locus and overlaps the TRalpha2 coding region. RevErbAalpha gene expression correlates with a high TRalpha1/TRalpha2 ratio in a number of tissues. Here we demonstrate that coexpression of RevErbAalpha and TRalpha regulates the TRalpha1/TRalpha2 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.