Tricarboxylic Acid Cycle Metabolites as Mediators of DNA Methylation Reprogramming in Bovine Preimplantation Embryos

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Ispada, Jessica ; da Fonseca Junior, Aldcejam Martins ; de Lima, Camila Bruna ; dos Santos, Erika Cristina ; Fontes, Patricia Kubo ; Gouveia Nogueira, Marcelo Fabio ; da Silva, Vinicius Lourenco ; Almeida, Fernanda Nascimento ; Leite, Saul de Castro ; Chitwood, James Lee ; Ross, Pablo Juan ; Milazzotto, Marcella Pecora

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 18, p. 16-pg., 2020-09-01.

Resumo

In many cell types, epigenetic changes are partially regulated by the availability of metabolites involved in the activity of chromatin-modifying enzymes. Even so, the association between metabolism and the typical epigenetic reprogramming that occurs during preimplantation embryo development remains poorly understood. In this work, we explore the link between energy metabolism, more specifically the tricarboxylic acid cycle (TCA), and epigenetic regulation in bovine preimplantation embryos. Using a morphokinetics model of embryonic development (fast- and slow-developing embryos), we show that DNA methylation (5mC) and hydroxymethylation (5hmC) are dynamically regulated and altered by the speed of the first cleavages. More specifically, slow-developing embryos fail to perform the typical reprogramming that is necessary to ensure the generation of blastocysts with higher ability to establish specific cell lineages. Transcriptome analysis revealed that such differences were mainly associated with enzymes involved in the TCA cycle rather than specific writers/erasers of DNA methylation marks. This relationship was later confirmed by disturbing the embryonic metabolism through changes in alpha-ketoglutarate or succinate availability in culture media. This was sufficient to interfere with the DNA methylation dynamics despite the fact that blastocyst rates and total cell number were not quite affected. These results provide the first evidence of a relationship between epigenetic reprogramming and energy metabolism in bovine embryos. Likewise, levels of metabolites in culture media may be crucial for precise epigenetic reprogramming, with possible further consequences in the molecular control and differentiation of cells. (AU)

• Processo FAPESP: 12/50533-2 - GIFT: melhoramento genômico de características relacionadas com a fertilização em gado bovino dinamarquês e brasileiro
• Beneficiário: Marcelo Fábio Gouveia Nogueira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/11668-6 - Metaboloepigenética: Interrelação entre o metabolismo energético e a metilação do DNA em embriões bovinos
• Beneficiário: Jéssica Ispada
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/18384-0 - Metaboloepigenética: o estudo do desenvolvimento de embriões bovinos sob uma nova ótica
• Beneficiário: Marcella Pecora Milazzotto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/03381-0 - Estresse celular e sua relação com a cinética de desenvolvimento de embriões bovinos produzidos in vitro
• Beneficiário: Marcella Pecora Milazzotto
• Modalidade de apoio: Auxílio à Pesquisa - Regular