Multiple stage-dependent roles for histone deacetylases during amphibian embryogenesis: implications for the involvement of extracellular matrix remodeling.

Histone acetylation has long been implicated in the regulation of gene expression. Recently, a number of histone acetyltransferase and histone deacetylase genes have been identified and cloned. Molecular studies have shown that these enzymes influence transcriptional regulation as components of cofactor complexesthat interact with diversetranscription factors. However, relatively little is known about their function during development. Here, we make use of the ability to manipulate Xenopus laevis embryos in vitro to study the role of histone deacetylases in development. We first demonstrate that the histone deacetylase Rpd3 and its associated co-repressor Sin3A are coordinately expressed during embryogenesis. Rpd3 and Sin3A are known to be part of at least one large corepressor complex, which is involved in transcriptional regulation by many transcription factors, suggesting that deacetylase activity is important for embryogenesis through transcriptional regulation. Indeed, treating developing embryos with a specific histone deacetylase inhibitor, trichostatin A (TSA), leads to embryonic lethality with severe defects in the head and tail regions. Furthermore, the effects of TSA are stage-dependent with the severity of the defects decreasing when treatment is initiated at later stages. On the other hand, a sharp bend (kink) develops in the tail even when TSA treatment begins at tadpole hatching. We provide evidence that this tail defect may be in part due to the TSA-dependent inhibition of the expression of the matrix metalloproteinase gene stromelysin-3, which has been implicated in tail development through extracellular matrix remodeling.