Inhibition of histone deacetylase activity by trichostatin A modulates gene expression during mouse embryogenesis without apparent toxicity.
Remodeling of the chromatin template by inhibition of histone deacetylase (HDAC) activities represents a major goal for transcriptional therapy in neoplastic diseases. Recently, a number of specific and potent HDAC-inhibitors that modulate in vitro cell growth and differentiation have been developed. In this study we analyzed the effect of trichostatin A (TSA), a specific and potent HDAC-inhibitor, on mouse embryos developing in vivo. When administered i.p. to pregnant mice (at a concentration of 0.5-1 mg/kg) at postimplantation stages (embryonic day 8 to embryonic day 10), TSA was not toxic for the mother and did not cause any obvious malformation during somitogenesis or at later stages of development. Treated embryos were born at similar frequency and were indistinguishable from control animals, developed normally, and were fertile. Interestingly, embryos from TSA-treated mice killed during somitogenesis were modestly but consistently larger than control embryos and presented an increased (+2 to +6) number of somites. This correlated with an increased acetylation of histone H4, the number of somites expressing the myogenic factor Myf-5, and the expression of Notch, RARalpha2, and RARbeta2 mRNAs. These data indicate that the effects of TSA on transcription: (a) are not toxic for the mother; (b) transiently accelerated growth in mouse embryos without perturbing embryogenesis; and (c) do not result in teratogenesis, at least in rodents. Thus, TSA might represent a nontoxic and effective agent for the transcriptional therapy of neoplasia.
Nervi
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C
Department of Histology and Medical Embryology, University of Rome La Sapienza, Italy. clara.nervi@uniroma1.it
Borello
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U
Fazi
F
F
Buffa
V
V
Pelicci
P G
PG
Cossu
G
G
D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006128:Growth / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000633:toxicity*; D051379:Mice; D011247:Pregnancy
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A