Histone acetylation influences thyroid hormone and retinoic acid-mediated gene expression

Thyroid hormone (T3) and retinoic acid (RA) receptors regulate transcription of the rat growth hormone (GH) gene through binding to a common hormone response element (HRE) in the promoter. We have investigated the effect of histone acetylation on hormone-dependent expression of the rat GH gene. We examined the effect of butyrate, which induces histone hyperacetylation, and trichostatin A (TSA), a highly specific inhibitor of histone deacetylases. GH-mRNA levels were significantly increased in pituitary GH4C1 cells incubated with T3 and RA, and this response was further stimulated in the presence of 1 mM butyrate. The effect of butyrate was mimicked by TSA. Butyrate and TSA also enhanced the activity of recombinant constructs containing the GH promoter directing chloramphenicol acetyl transferase (CAT) reporter gene expression. CAT activity increased by 4- to 8-fold after incubation with 1 nM T3 and 1 mu M RA, and this response was stimulated 2- to 4-fold further in the presence of 0.25 mM butyrate. This concentration of butyrate did not influence basal expression of CAT. TSA produced a dose-dependent increase of CAT activity in the absence of ligands, and between 5 and 200 nM potentiated the effect of T3 and RA. These compounds also increased the hormonal response of constructs in which the HRE was linked to heterologous [mouse mammary tumor virus (MMTV) and thymidine kinase (TK)] promoters. With butyrate >1 mM, basal activity of the GH promoter increased by more than 10-fold and the effect of T3 and RA was no longer observed. Overexpression of T3 receptors was able to counteract the stimulation of basal CAT levels caused by butyrate. Thus, in the absence of ligand, the T3 receptor acts as a constitutive repressor of gene expression. Upon binding of the hormone, the T3 receptor is converted into an activator. Our findings suggest that histone acetylation, which alters chromatin structure, may play an important role in hormone-mediated transcriptional regulation.