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[Cancer Research 61, 1247-1249, February 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Inhibition of Histone Deacetylase Activity by Trichostatin A Modulates Gene Expression during Mouse Embryogenesis without Apparent Toxicity1

Clara Nervi2, Ugo Borello, Francesco Fazi, Viviana Buffa, Pier Giuseppe Pelicci and Giulio Cossu2

Department of Histology and Medical Embryology, University of Rome, 00161 Rome [C. N., U. B., F. F., V. B., G. C.]; Stem Cell Research Institute, Dibit, 20132 Milan [U. B., G. C.]; and European Institute of Oncology, Department of Experimental Oncology, 20141 Milan [P. G. P.], Italy


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
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, RAR{alpha}2, and RARß2 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.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
A common multiprotein complex containing catalytically active HDACs3 mediates the transcriptional repression of transcription factors such as Mad/MAX, E2F, YY1, or members of the steroid/thyroid receptor superfamilies (1, 2, 3) . Deacetylation of nucleosomal core histone tails by the HDACs leads to a chromatin conformation that inhibits transcription, whereas histone acetylation results in transcriptional activation after local chromatin remodeling and recruitment of the RNA polymerase II complexes (2 , 3) .

Drugs modulating the acetylation status of histones have been proposed recently as a novel approach for the molecular treatment of cancer (4 , 5) . In AMLs, different chromosomal translocation-generated fusion gene products, such as PML/RAR{alpha}, PLZF/RAR{alpha}, and AML1/ETO, induce an abnormal regulation of HDAC activities, an event that plays a crucial role in the pathogenesis and maintenance of the transformed phenotype (6, 7, 8, 9, 10) . In agreement with these biological findings, clinical efficacy has been reported for the HDAC-inhibitor butyrate and its analogue phenylbutyrate in the treatment of AML and in a RA-resistant acute promyelocytic leukemia patient (11 , 12) . A potential use of HDAC-inhibitors is also foreseen for cancer, with inactivation of tumor suppressor genes attributable to the hypermethylation of their promoters. HDAC, indeed, is involved in the transcriptional silencing of methylated promoters (3 , 13) .

However, the availability of HDAC-inhibitors for clinical use is limited. Butyrates and their derivatives have limited toxicity, but they act as nonspecific, transient, and reversible HDAC-inhibitors. Recently, a number of highly specific, stable, and more potent inhibitors of HDAC activities have been developed (14) . Among these, TSA is one of the most active and studied. TSA has been found effective in modulating cell growth and differentiation in a number of in vitro systems, including carcinoma cell lines and myeloid leukemias, suggesting its potential use in transcriptional therapy of neoplasia (4 , 6 , 15, 16, 17) .

A major issue concerning transcriptional therapy with HDAC-inhibitors is the expected toxicity of these compounds. Indeed, the general involvement of HDACs in a variety of fundamental cellular processes suggests a wide range of biological effects for HDAC-inhibitors when used as drugs. In support of this view, a recent publication reported malformations in embryos treated with TSA in vitro (18) . However, a systematic analysis of the toxicity of HDAC-inhibitors during embryo development and in the adult life is lacking. In this study, we investigated the effect of TSA treatment in adult mice and during embryonic development and report that, despite its wide effects on histone acetylation and gene expression, TSA is not toxic and does not perturb mouse embryonic or postnatal development.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
CD1 pregnant mice (E 8, 9, and 10) received i.p. injections of 15 µg of TSA (WAKO Chemicals, Neuss, Germany) in 0.2 ml of DMSO (Sigma, Milano, Italy) or 0.2 ml of vehicle alone. In some experiments, the same dose was repeated after 24 h. At the time indicated, mice were killed, and the embryos were observed under a dissecting stereomicroscope to evaluate their viability, the presence of external malformations, and the number of somites. Embryos were then fixed in 4% paraformaldehyde for histology, X-Gal staining, and whole-mount in situ hybridization using Notch and RAR{alpha}1, -{alpha} 2, and -ß 2 antisense probes (19, 20, 21, 22) . Immunoblot analysis was performed on total embryo homogenates (60 µg) using anti-histone H4 and anti-acetylated histone H4 antibodies (Upstate Biotecnology). Densitrometic analysis was performed using the Advanced Image Data Analyzer (Raytest, Milan, Italy).


   Results and Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
The administration of a single TSA i.p. injection (15 µg) to pregnant CD1 outbred mice at E 8, 9, or 10 did not result in any apparent toxicity for the mother and did not cause embryo malformations or defects at birth or during the animals’ postnatal growth. Animals treated in utero developed to normal adult size and were fertile. Observation under a dissecting microscope revealed that 6- to 24-h TSA treatment of the mother constantly resulted in a slight, but statistically significant, increase in the number of somites in E 8.5-, 9-, or 9.5-treated embryos. Treatment with the vehicle (DMSO) induced no variations in any of the parameters analyzed (control; Fig. 1ACitation ). From E 8 to E 11, the number of somites represents the simplest and most faithful indicator of the embryonic stage of development.



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  		Fig. 1. A, number of somites in control (open symbols) and TSA-treated (closed symbols) embryos. The number of somites was counted, including the two occipital somitomers. Time of killing is indicated in the upper abscissa, and the length of previous TSA treatment is indicated in the lower abscissa. B, immunoblot analysis of the acetylation status of histone H4 was performed in total embryo extracts using the antiacetylated histone H4 antibody. Representative samples from three controls and TSA-treated embryos are shown. Expression of histone H4 was used to control the histone H4 acetylation levels. C, ratio Ac-H4:H4 histone in control (open bars) and in TSA-treated embryos (dashed bars).

 
We investigated whether the effect of TSA on embryos correlated with modifications of histone acetylation. Fig. 1BCitation shows an immunoblotting analysis of extracts prepared from three control and three TSA-treated embryos using an antibody that recognizes the acetylated form of histone H4. Although these forms were already detectable in control whole embryos, they appeared more abundant in embryos from TSA-treated mice; this did not reflect an increased accumulation of the H4 protein as shown by an antibody recognizing the histone H4 protein in the same samples (Fig. 1, B and C)Citation . It appeared therefore that in vivo treatment with TSA affects mammalian embryonic development but is not embryotoxic. This is at variance with a previous study (18) that showed malformations in early postimplantation embryos exposed in vitro to TSA. In this case, direct exposure to high TSA concentrations of embryos, which in culture develop under critical conditions, may have caused effects that are not seen after exposure in vivo. Indeed, even repeating TSA administration after 24 h did not result in apparent abnormalities in treated embryos. This discrepancy might be attributable to the actual concentrations of TSA, which may not be directly comparable between the two studies.

During vertebrate embryogenesis, somites are formed in a strict cranio-caudal order by the successive segmentation of the paraxial mesoderm flanking the neural tube (23) . Caudal to the most recently formed somite, the paraxial mesoderm appears morphologically unsegmented. Subsequently, somites become compartmentalized into a dorsal epithelial dermomyotome (future muscle and dermis) and a ventral mesenchymal sclerotome (future vertebral column and ribs). We therefore evaluated whether i.p. injection of TSA could modulate in vivo the expression of Myf-5 and Notch, two genes involved in somitogenesis (24) . Myf-5 is a basic-helix-loop-helix transcriptional regulator of muscle determination and is a useful marker of somites that contain cells already committed to skeletal myogenesis (25) . Once formed, the somites follow a normal process of maturation, and Myf-5 is activated at the proper time, i.e., in the second- to third- last-formed somite. Myf-5 expression was evaluated by staining for X-Gal Myf-5/nlacZ (Myf-5a2+/-) embryos, where the nLacZ reporter gene has been targeted into the Myf-5 locus (26) . Fig. 2Citation (A and B) shows that both the total number of somites and the number of Myf-5-expressing somites (revealed in blue by X-Gal staining in A) were consistently increased in TSA-treated embryos.



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  		Fig. 2. Gene expression in TSA-treated embryos. Note than in all panels, TSA-treated embryos are slightly larger than control embryos. A, whole mount in situ hybridization for Notch on a control and a TSA-treated embryo, also stained for Myf-5 expression by X-Gal (28) . Note that the TSA-treated embryo has two additional somites expressing Myf-5. This is quantified in B, where the total number of somites (dashed bars) and the number of X-Gal somites expressing Myf-5 (closed bars) are shown. Somites were scored as Myf5+ when they contained in excess of five X-Gal+ nuclei. Treated embryos had a higher level of Notch expression in the presomitic mesoderm; this is more evident in C, where only the dissected caudal portion of embryos hybridized with the Notch probe are shown. D, whole-mount in situ hybridization for RAR{alpha}1 in control and TSA-treated E-9.5 embryos. Note comparable levels of expression throughout the mesoderm and in the branchial arches. E, whole-mount in situ hybridization for RAR{alpha}2 in control and TSA-treated E-9.5 embryos. TSA-treated embryos expressed higher levels of RAR{alpha}2 in the cranial spinal cord and in the hindbrain. F, whole-mount in situ hybridization for RARß2 in two controls (above) and in two TSA-treated (below) E-9.5 embryos. Note that TSA-treated embryos express higher levels of RARß in the presomitic mesoderm. C, control.

 
By whole-mount in situ hybridization we found that Notch expression was increased in the presomitic paraxial mesoderm of TSA-treated embryos (revealed in purple by the antisense probe; Fig. 2ACitation ; a higher magnification of the presomitic mesoderm is shown in C). Because Notch and members of its signal transduction pathway control numerous cell-fate decisions during development and are involved in the patterning of somites (24) , its increased expression might accelerate this process, resulting in the additional somites formed in response to TSA treatment. Together these results show that TSA treatment during the postimplantation stage, when critical morphogenetic events occur, results in the increased expression of Notch, accelerated formation of somites, and normal commitment to myogenesis.

Recently, a number of studies showed that unliganded nuclear receptors, such as the RARs (RAR{alpha}, -ß, and -{gamma}), recruit the nuclear corepressors N-CoR and SMRT that associate with adapter proteins like Sin3 and histone deacetylases (HDAC1 and HDAC2) to form a transcriptional repressor complex at the response element of RA target genes (RAREs). (1 , 2) . Ligand binding releases corepressors and HDACs and recruits transcriptional adapters and coactivators that include histone acetyltransferase activities such as p300/CBP, ACTR, and TIF2 (1 , 2) . Interestingly, cells derived from mice lacking a functional p300 gene proliferate poorly and display specific transcriptional defects of RA signaling (27) . Each RAR gene generates distinct mRNA isoforms by the use of different promoters and alternative splicing. The RAR isoforms RAR{alpha}2 and RARß2 posses a RARE in their promoters that is responsible for their RA inducibility occurring through a HDAC-dependent signaling pathway (1 , 20 , 21) . The RARE is not present in the promoter of the RAR{alpha}1 isoform, which, at variance with RAR{alpha}2, is expressed constitutively in mouse adult tissues as a housekeeping gene and is widely distributed during mouse embryogenesis (20, 21, 22) . We therefore examined by whole-mount in situ hybridization the expression levels of RAR{alpha}1, RAR{alpha}2, and RARß2 in control and in TSA-treated E-9.5 mouse embryos. Fig. 2DCitation shows similar levels of RAR{alpha}1 transcript in the expected sites of expression, such as the branchial arches, somitic mesoderm, and limb buds of embryos from control and TSA-treated mice. In contrast, significantly higher levels of expression of RAR{alpha}2 in the spinal cord and hindbrain, as well as of RAR-ß2 in the presomitic mesoderm, could be detected in TSA-treated embryos when compared with control embryos. Thus, the HDAC-inhibitor TSA relieved a repressive activity associated with the HDAC-complex at the RARE of RA target genes.

In summary, the results presented in this study indicate that in vivo modulation of gene transcription by inhibition of HDAC activity by TSA treatment is neither toxic nor teratogenic, at least in rodents, suggesting that TSA might represent a novel and safe transcriptional therapeutical agent.


   ACKNOWLEDGMENTS
 
We thank S. Tajbakhsh for the Myf-5a2+/- mice and F. Grignani for helpful discussion and suggestions.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by grants from the Associazione Italiana Ricerca sul Cancro, Fondazione Cenci Bolognetti, the Ministero dell’Università e Ricerca Scientifica e Tecnologica, and European Community and Telethon. Back

2 To whom requests for reprints should be addressed, at Department of Histology and Medical Embryology, University of Rome, "La Sapienza," 00161 Rome, Italy. Tel: 39-06-497681026757; Fax: 39-06-4462854; E-mail: clara.nervi@uniroma1.it or giulio.cossu{at}uniroma1.it Back

3 The abbreviations used are: HDAC, histone deacetylase; AML, acute myeloid leukemia; TSA, trichostatin A; RA, retinoic acid; RAR, RA receptor; RARE, RA response element; E, embryonic day; X-Gal, 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside. Back

Received 8/ 7/00. Accepted 12/28/00.


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