HISTONE ACETYLATION INFLUENCES THYROID-HORMONE AND RETINOIC ACID-MEDIATED GENE-EXPRESSION

Thyroid hormone (T3) and retinoic acid (RA) receptors regulate transcr iption 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 t he rat GH gene. We examined the effect of butyrate, which induces hist one hyperacetylation, and trichostatin A (TSA), a highly specific inhi bitor of histone deacetylases. GH-mRNA levels were significantly incre ased in pituitary GH4C1 cells incubated with T3 and RA, and this respo nse was further stimulated in the presence of 1 mM butyrate. The effec t of butyrate was mimicked by TSA. Butyrate and TSA also enhanced the activity of recombinant constructs containing the GH promoter directin g chloramphenicol acetyl transferase (CAT) reporter gene expression. C AT activity increased by 4- to 8-fold after incubation with 1 nM T3 an d 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 n ot influence basal expression of CAT. TSA produced a dose-dependent in crease of CAT activity in the absence of ligands, and between 5 and 20 0 nM potentiated the effect of T3 and RA. These compounds also increas ed the hormonal response of constructs in which the HRE was linked to heterologous [mouse mammary tumor virus (MMTV) and thymidine kinase (T K)] 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 long er observed. Overexpression of T3 receptors was able to counteract the stimulation of basal CAT levels caused by butyrate. Thus, in the abse nce of ligand, the T3 receptor acts as a constitutive repressor of gen e expression. Upon binding of the hormone, the T3 receptor is converte d into an activator. Our findings suggest that histone acetylation, wh ich alters chromatin structure, may play an important role in hormone- mediated transcriptional regulation.