Histone deacetylase 3 (hdac3) is specifically required for liver development in zebrafish

Abstract

Histone deacetylases (HDACs) are key transcription regulators that function by deacetylating histones/transcription factors and modifying chromatin structure. In this work, we showed that chemical inhibition of HDACs by valproic acid (VPA) led to impaired liver development in zebrafish mainly by inhibiting specification, budding, and differentiation. Formation of exocrine pancreas but not endocrine pancreas was also inhibited. The liver defects induced by VPA correlate with suppressed total HDAC enzymatic activity, but are independent of angiogenesis inhibition. Gene knockdown by morpholino demonstrated that hdac3 is specifically required for liver formation while hdac1 is more globally required for multiple development processes in zebrafish including liver/exocrine pancreas formation. Furthermore, overexpression of hdac3 but not hdac1 partially rescued VPA induced small liver. One mechanism by which hdac3 regulates zebrafish liver growth is through inhibiting growth differentiation factor 11 (gdf11), a unique target of hdac3 and a member of the transforming growth factor beta family. Simultaneous overexpression or morpholino knockdown showed that hdac3 and gdf11 function antagonistically in zebrafish liver development. These results revealed a novel and specific role of hdac3 in liver development and the distinct functions between hdac1 and hdac3 in zebrafish embryonic development.

Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models

“…To aid in the identification and quantification of the zebrafish body curvature phenotype, we developed a computer algorithm that can reliably classify individual animals among group pictures automatically, making it feasible to perform large-scale HTS for compound suppressors in the future. Significantly, as VPA is a class I HDACs inhibitor (12)(13)(14) and hdac1 encodes a class I HDAC, our results indicate that class I HDACs play a critical role in PKD pathogenesis and suggest that HDAC inhibitors may be excellent drug candidates for PKD treatment.…”

“…As a pan-HDAC inhibitor, TSA targets both class I and class II HDACs, while VPA is known to be more specific toward class I HDACs (12)(13)(14). Interestingly, wild-type zebrafish embryos treated with TSA or VPA showed very similar phenotypes: in addition to ventrally curved body axis, they also showed lighter pigmentation (23) (Figs.…”

Biological Screening of Novel Derivatives of Valproic Acid for Anticancer and Antiangiogenic Properties

“…Besides interfering with angiogenic blood vessels formation, the compounds from valproylglycine hydrazide series also induced severe cardiac edema (Figure 1 black arrow in D). The cardiac edema has also been shown in previous studies which are HDAC mutant (Pillai et al, 2004;Yamaguchi et al, 2005) or embryos were treated with VPA or any other HDAC inhibitor (Farooq et al, 2008;Cao et al, 2009;Johnson et al, 2013). We have not analyzed the HDAC enzymatic activity with these compounds but most likely that the cardiac edema which is result of newly synthesized VPA derivatives could be due to their HDAC inhibition activity.…”

“…The zebrafish transgenic line (Tg: fli1:EGFP) y1 is an establish in vivo model to assess the antiangiogenic activity of synthetic compounds and natural products (Farooq et al, 2008;Lin et al, 2012;Tse et al, 2012;Yeh et al, 2012;Zhong et al, 2012;Hollenbach et al, 2013). The formation of inter-segmental blood vessels (Se) and sub-intestinal vein (Bohni et al, 2013) are the result of angiogenic process in zebrafish embryo (Isogai et al, 2003;Ellertsdottir et al, 2010).…”

“…Beside an effective epileptic drug VPA also inhibits angiogenesis both in vitro and in vivo (Michaelis et al, 2004;Zgouras et al, 2004;Farooq et al, 2008;Kitazoe et al, 2009;Osuka et al, 2012). Being a smaller in size and remarkable therapeutic potential, several synthetic compounds have been designed as structural derivatives of VPA with improved bioactivities.…”