Involvement of histone deacetylase at two distinct steps in gene regulation during intestinal development in Xenopus laevis.

Abstract

Amphibian metamorphosis is marked by dramatic thyroid hormone (T(3))-induced changes including de novo morphogenesis, tissue remodeling and organ resorption through programmed cell death. These changes involve cascades of gene regulation initiated by thyroid hormone and its receptors. Previous studies suggest that chromatin remodeling involving changes in core histone acetylation plays a fundamental role in transcriptional regulation. A basic model has been suggested where targeted histone deacetylation is involved in transcriptional repression and histone acetylation is involved in transcriptional activation. On the other hand, the developmental roles of histone acetylation remain to be elucidated. Here we demonstrate that tadpole treatment with trichostatin A, a specific potent histone deacetylase inhibitor, blocks metamorphosis. Gene expression analyses show that trichostatin A induces the release of T(3)-response gene repression without affecting T(3)-induction of direct T(3)-response genes. However, the drug blocks the regulation of late T(3)-response genes, which may be responsible for its inhibitory effects on metamorphosis. These data support a role of deacetylases in transcriptional repression by unliganded T(3) receptor during premetamorphosis and another role at a downstream step of the gene regulation cascade induced by T(3) during metamorphosis.