Cargando…
Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads
BACKGROUND: 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 approv...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721477/ https://www.ncbi.nlm.nih.gov/pubmed/29216900 http://dx.doi.org/10.1186/s13072-017-0168-7 |
_version_ | 1783284814425620480 |
---|---|
author | Ribas, Laia Vanezis, Konstantinos Imués, Marco Antonio Piferrer, Francesc |
author_facet | Ribas, Laia Vanezis, Konstantinos Imués, Marco Antonio Piferrer, Francesc |
author_sort | Ribas, Laia |
collection | PubMed |
description | BACKGROUND: 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). RESULTS: 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 anaemia or the Wnt signalling pathways were downregulated. Furthermore, an overall inhibition of genes implicated in epigenetic regulatory mechanisms (e.g. dnmt1, dicer, cbx4) was also observed. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13072-017-0168-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5721477 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57214772017-12-11 Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads Ribas, Laia Vanezis, Konstantinos Imués, Marco Antonio Piferrer, Francesc Epigenetics Chromatin Research BACKGROUND: 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). RESULTS: 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 anaemia or the Wnt signalling pathways were downregulated. Furthermore, an overall inhibition of genes implicated in epigenetic regulatory mechanisms (e.g. dnmt1, dicer, cbx4) was also observed. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13072-017-0168-7) contains supplementary material, which is available to authorized users. BioMed Central 2017-12-08 /pmc/articles/PMC5721477/ /pubmed/29216900 http://dx.doi.org/10.1186/s13072-017-0168-7 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Ribas, Laia Vanezis, Konstantinos Imués, Marco Antonio Piferrer, Francesc Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads |
title | Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads |
title_full | Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads |
title_fullStr | Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads |
title_full_unstemmed | Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads |
title_short | Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads |
title_sort | treatment with a dna methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721477/ https://www.ncbi.nlm.nih.gov/pubmed/29216900 http://dx.doi.org/10.1186/s13072-017-0168-7 |
work_keys_str_mv | AT ribaslaia treatmentwithadnamethyltransferaseinhibitorfeminizeszebrafishandinduceslongtermexpressionchangesinthegonads AT vaneziskonstantinos treatmentwithadnamethyltransferaseinhibitorfeminizeszebrafishandinduceslongtermexpressionchangesinthegonads AT imuesmarcoantonio treatmentwithadnamethyltransferaseinhibitorfeminizeszebrafishandinduceslongtermexpressionchangesinthegonads AT piferrerfrancesc treatmentwithadnamethyltransferaseinhibitorfeminizeszebrafishandinduceslongtermexpressionchangesinthegonads |