Amphibians such as Xenopus laevis and Ambystoma mexicanum are capable of whole 
structure regeneration. However, transcriptional control over these events is 
not well understood. Here, we investigate the role of histone deacetylase (HDAC) 
enzymes in regeneration using HDAC inhibitors. The class I/II HDAC inhibitor 
valproic acid (VPA) inhibits tail regeneration in embryos of the anuran 
amphibian Xenopus laevis, confirming a recent report by others (Tseng et al., 
2011). This inhibition correlates with a sixfold reduction in endogenous HDAC 
activity. VPA also inhibited tail regeneration in post-refractory stage Xenopus 
larvae and larvae of the urodele A. mexicanum (axolotl). Furthermore, Xenopus 
limb regeneration was also significantly impaired by post-amputation treatment 
with VPA, suggesting a general requirement for HDAC activity in the process of 
appendage regeneration in amphibians. The most potent inhibition of tail 
regeneration was observed following treatment with VPA during the wound healing, 
pre-blastema phase. A second HDAC inhibitor, sodium butyrate, was also shown to 
inhibit tail regeneration. While both VPA and sodium butyrate are reported to 
block sodium channel function as well as HDACs, regeneration was not inhibited 
by valpromide, an analogue of VPA that lacks HDAC inhibition but retains sodium 
channel blocking activity. Finally, although VPA is a known teratogen, we show 
that neither tailbud nor limb bud development are affected by exposure to this 
compound. We conclude that histone deacetylation is specifically required for 
the earliest events in appendage regeneration in amphibians, and suggest that 
this may act as a switch to trigger re-expression of developmental genes.