Development to term of cloned cattle derived from donor cells treated with valproic acid

Cloning of mammals by somatic cell nuclear transfer (SCNT) is still plagued by low efficiency. The epigenetic modifications established during cellular differentiation are a major factor determining this low efficiency as they act as epigenetic barriers restricting reprogramming of somatic nuclei. I...

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Published in:PloS one 2014-06, Vol.9 (6), p.e101022
Main Authors: Sangalli, Juliano Rodrigues, Chiaratti, Marcos Roberto, De Bem, Tiago Henrique Camara, de Araújo, Reno Roldi, Bressan, Fabiana Fernandes, Sampaio, Rafael Vilar, Perecin, Felipe, Smith, Lawrence Charles, King, Willian Allan, Meirelles, Flávio Vieira
Format: Article
Language:English
Subjects:
Acetylation
Acetylation - drug effects
Acids
Animal genetic engineering
Animals
Biology and Life Sciences
Birth
Bovidae
Calves
Cattle
Cell differentiation
Cell Differentiation - drug effects
Cell Proliferation - drug effects
Chromatin
Cloning
Cloning, Organism - methods
Deoxyribonucleic acid
DNA
DNA methylation
DNA Methylation - drug effects
Efficiency
Embryonic Development - drug effects
Embryos
Epigenetic inheritance
Fibroblasts
Gene expression
Gestation
Histone deacetylase
Histone Deacetylase Inhibitors - pharmacology
Histones - metabolism
Implantation
Insulin-like growth factor II receptors
Methylation
Nuclear transfer
Nuclear Transfer Techniques
Nuclei
Oct-4 protein
Octamer Transcription Factor-3 - genetics
Octamer Transcription Factor-3 - metabolism
Receptor, IGF Type 2 - genetics
Receptor, IGF Type 2 - metabolism
Somatic cell nuclear transfer
Stem cells
Valproic acid
Valproic Acid - pharmacology
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Summary:Cloning of mammals by somatic cell nuclear transfer (SCNT) is still plagued by low efficiency. The epigenetic modifications established during cellular differentiation are a major factor determining this low efficiency as they act as epigenetic barriers restricting reprogramming of somatic nuclei. In this regard, most factors that promote chromatin decondensation, including histone deacetylase inhibitors (HDACis), have been found to increase nuclear reprogramming efficiency, making their use common to improve SCNT rates. Herein we used valproic acid (VPA) in SCNT to test whether the treatment of nuclear donor cells with this HDACi improves pre- and post-implantation development of cloned cattle. We found that the treatment of fibroblasts with VPA increased histone acetylation without affecting DNA methylation. Moreover, the treatment with VPA resulted in increased expression of IGF2R and PPARGC1A, but not of POU5F1. However, when treated cells were used as nuclear donors no difference of histone acetylation was found after oocyte reconstruction compared to the use of untreated cells. Moreover, shortly after artificial activation the histone acetylation levels were decreased in the embryos produced with VPA-treated cells. With respect to developmental rates, the use of treated cells as donors resulted in no difference during pre- and post-implantation development. In total, five clones developed to term; three produced with untreated cells and two with VPA-treated cells. Among the calves from treated group, one stillborn calf was delivered at day 270 of gestation whereas the other one was delivered at term but died shortly after birth. Among the calves from the control group, one died seven days after birth whereas the other two are still alive and healthy. Altogether, these results show that in spite of the alterations in fibroblasts resulting from the treatment with VPA, their use as donor cells in SCNT did not improve pre- and post-implantation development of cloned cattle.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0101022