Effect of serum triiodothyronine on regulation of cardiac gene expression: role of histone acetylation

Abstract

Thyroid hormone regulates the transcription of several important cardiac genes. Although the thyroid gland produces predominantly thyroxine (T4), it is triiodothyronine (T3) that is transported across the sarcolemma and binds to nuclear thyroid hormone receptor proteins; yet various studies suggest that serum T3 levels do not accurately reflect cellular T3 action. To address this question, we studied the dose-response relationship of T3 administered by constant infusion in hypothyroid animals with the simultaneous in vivo transcription rate of the cardiac-specific α-myosin heavy chain (MHC) gene, measured by quantitating α-MHC heteronuclear (hn)RNA content. Constant infusion of 4 μg T3·kg body wt−1·day−1 for 3 days normalized serum T3 and restored transcription to euthyroid levels; in contrast, daily injections of the same dose increased α-MHC transcription by only 55% of that obtained by infusion. Although infusion of T3 at 1.25 μg T3·kg body wt−1·day−1 was not sufficient to restore serum T3 to normal, it was capable of restoring transcription to normal at 3 days, but when administered for 12 days, transcription of α-MHC was found to be 50% of euthyroid levels, demonstrating a decreased sensitivity to T3 over time. Treatment with trichostatin A (TSA) to inhibit histone deacetylation increased levels of total nuclear acetylated histone H4 by almost 50% but was without effect on the real-time PCR measures of α-MHC hnRNA. TSA administered together with T3 (10 μg T3/kg body wt) significantly increased transcription of α-MHC after 30 h, thus demonstrating a potential role for histones as cofactors in the T3 regulation of cardiac α-MHC transcription.