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| Status |
Public on Nov 30, 2017 |
| Title |
Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads |
| Organism |
Danio rerio |
| Experiment type |
Expression profiling by array
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| Summary |
The role of epigenetic modifications such as DNA methylation during vertebrate sexual development is far from being clear. Using the zebrafish model, we tested the effects of one of the most common DNA methyltransferase (dnmt) inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), which is approved for the treatment of acute myeloid leukaemia and is under active investigation for the treatment of solid tumours. Several dose-response experiments were carried out during two periods, including not only the very first days of development (0–6 days post fertilization, dpf), as done in previous studies, but also, and as a novelty, the period of gonadal development (10–30 dpf).
Early treatment with 5-aza-dC altered embryonic development, delayed hatching and increased teratology and mortality, as expected. The most striking result, however, was an increase in the number of females, suggesting that alterations induced by 5-aza-dC treatment can affect sexual development as well. Results were confirmed when treatment coincided with gonadal development. In addition, we also found that the adult gonadal transcriptome of 5-aza-dC-exposed females included significant changes in the expression of key reproduction-related genes (e.g., cyp11a1, esr2b and figla), and that several pro-female related pathways such as the Fanconi anemia or the Wnt signaling pathways were downregulated. Furthermore, an overall inhibition of genes implicated in epigenetic regulatory mechanisms (e.g., dnmt1, dicer, cbx4) was also observed. Taken together, our results indicate that treatment with a DNA methylation inhibitor can also alter the sexual development in zebrafish, with permanent alterations of the adult gonadal transcriptome, at least in females. Our results show the importance of DNA methylation for proper control of sexual development, open new avenues for the potential control of sex ratios in fish (aquaculture, population control), and call attention to possibly hidden long-term effects of dnmt therapy when used, for example, in the treatment of prepuberal children affected by some types of cancer.
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| Overall design |
At 10 days post fertilization, fish were divided in 2.8-liter tanks in static conditions. The 5-aza-CdR effects were studied during gonadal development (10–30 dpf) at a concentration of 75 µM. 5-aza-CdR was added into the water tank and half of the water with the corresponding 5-aza-CdR concentration was changed three times a week during the period of treatment. At 90 dpf fish were sacrified and gonads were dissected and flash frozen. RNA was extracted by Trizol (Sigma) and were hybridized individually in 4x44K Agilent platform (G2519F).
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| Contributor(s) |
Ribas L, Vanezis K, Imues MA, Piferrer F |
| Citation(s) |
29216900 |
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| Submission date |
Jan 10, 2017 |
| Last update date |
Mar 02, 2018 |
| Contact name |
Laia Ribas |
| E-mail(s) |
lribas@icm.csic.es, laiaribas79@gmail.com
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| Organization name |
Institut de Ciencies del Mar
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| Street address |
Passeig Maritim 37-49
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| City |
Barcelona |
| ZIP/Postal code |
08003 |
| Country |
Spain |
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| Platforms (1) |
| GPL14688 |
Agilent-026437 D. rerio (Zebrafish) Oligo Microarray V3 (Feature Number version) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA360816 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE93367_RAW.tar |
64.5 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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