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

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 18, p. 16-pg., 2020-09-01.

Abstract

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)

• FAPESP's process: 12/50533-2 - GIFT: genomic improvement of fertilization traits in Danish and Brazilian cattle
• Grantee: Marcelo Fábio Gouveia Nogueira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/11668-6 - Metaboloepigenetics: Interrelationships between energetic metabolism and DNA methylation in bovine embryos
• Grantee: Jéssica Ispada
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/18384-0 - METABOLOEPYGENETICS: THE STUDY OF THE BOVINE EMBRYO DEVELOPMENT UNDER A NEW PERSPECTIVE
• Grantee: Marcella Pecora Milazzotto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/03381-0 - CELLULAR STRESS AND ITS RELATION WITH THE KINECTICS OF IN VITRO PRODUCED BOVINE EMBRYOS
• Grantee: Marcella Pecora Milazzotto
• Support Opportunities: Regular Research Grants