n-Butyrate increases the level of thyroid hormone nuclear receptor in non-pituitary cultured cells

The thyroid hormone nuclear receptor is a chromatin-associated protein regulating expression of specific genes. Acetylation of nucleosomal core histones is thought to be one of the factors regulating transcriptional activity of chromatin, and it is suggested that this reaction negatively regulates thyroid hormone receptor levels in GH1 cells (Samuels, H.H., Stanley, F., Casanova, J., and Shao, T. C. J. Biol. Chem. 255, 2499-2508). In the present study, we found that n-butyrate, a potent inhibitor of histone deacetylase, increases thyroid hormone receptor levels in three distinct non-pituitary cells without changing binding affinity. This effect appeared within 30 min and reached a plateau (240% of control) after a 6-h treatment, before important cellular functions were affected. This effect was time-dependent, dose-dependent, reversible, and paralleled the changes in the electrophoretic mobilities of histones H3 and H4. n-Butyrate prolonged the receptor half-life, and this prolongation corresponded to the increase of receptor levels. Thyroid hormone did not reduce its own receptor levels or influence the effect of n-butyrate. Considering the difference between GH1 cells and non-pituitary cells in the regulation of thyroid hormone receptor levels, our observations, together with those of Samuels et al., suggest the possibility that the acetylation of chromatin-associated proteins has a physiological significance in the regulation of thyroid hormone nuclear receptor levels.