Erasing gametes to write blastocysts: metabolism as the new player in epigenetic reprogramming

Thematic Section: 36th Annual Meeting of the Association of Embryo Technology in Europe (AETE) • Anim. Reprod. 17 (3) • 2020 • https://doi.org/10.1590/1984-3143-AR2020-0015 copy

Erasing gametes to write blastocysts: metabolism as the new player in epigenetic reprogramming

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Understanding preimplantation embryonic development is crucial for the improvement of assisted reproductive technologies and animal production. To achieve this goal, it is important to consider that gametes and embryos are highly susceptible to environmental changes. Beyond the metabolic adaptation, the dynamic status imposed during follicular growth and early embryogenesis may create marks that will guide the molecular regulation during prenatal development, and consequently impact the offspring phenotype. In this context, metaboloepigenetics has gained attention, as it investigates the crosstalk between metabolism and molecular control, i.e., how substrates generated by metabolic pathways may also act as players of epigenetic modifications. In this review, we present the main metabolic and epigenetic events of pre-implantation development, and how these systems connect to open possibilities for targeted manipulation of reproductive technologies and animal production systems.

Keywords:
embryo; metabolism; epigenetic; metaboloepigenetic

Authorship

Marcella Pecora Milazzotto ^**Corresponding author: marcella.milazzotto@ufabc.edu.br

Laboratório de Epigenética e Metabolismo Embrionário, Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, BrasilUniversidade Federal do ABCBrasilSanto André, SP, BrasilLaboratório de Epigenética e Metabolismo Embrionário, Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brasil

Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, BrasilUniversidade de São PauloBrasilSão Paulo, SP, BrasilInstituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brasil

http://orcid.org/0000-0003-0933-3066

Camila Bruna de Lima

Département des Sciences Animales, Centre de Recherche en Reproduction, Développement et Santé Intergénérationnelle, Faculté des Sciences de l’Agriculture et de l’Alimentation, Université Laval, Quebec, CanadaUniversité LavalCanadaQuebec, CanadaDépartement des Sciences Animales, Centre de Recherche en Reproduction, Développement et Santé Intergénérationnelle, Faculté des Sciences de l’Agriculture et de l’Alimentation, Université Laval, Quebec, Canada

http://orcid.org/0000-0001-6043-0190

Aldcejam Martins da Fonseca Junior

http://orcid.org/0000-0003-2646-9168

Erika Cristina dos Santos

http://orcid.org/0000-0002-3326-4980

Jessica Ispada

http://orcid.org/0000-0001-6129-3116

*Corresponding author: marcella.milazzotto@ufabc.edu.br

Conflicts of interest: The authors have no conflict of interest to declare.

Author contributions MPM: Conceptualization, Resources, Supervision, Writing; JI: Formal analysis, Resources, Writing; CBL: Formal analysis, Resources, Writing; ECS: review and editing; AMFJ: review and editing.

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (4)

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Figure 1
Embryo development requires the activation of specific pathways to produce energy. Prior to compactation, embryo metabolism is mainly supported by pyruvate and amino acids, metabolized through tricarboxylic acid (TCA) cycle and oxidative phosphorylation. At the time of compactation, embryo increases its energetic demand especially for increasing biosynthesis and cell proliferation, but also for the formation and expansion of blastocoel, and hatching. At this time, glucose is metabolized with greater efficiency by two main pathways: the pentose phosphate pathway (PPP) (important for biomass and nucleotide generation) and the glycolytic pathway (that increases ATP production and pyruvate synthesis). At the end of the glycolytic pathway, pyruvate can also be converted to lactate, even in the presence of oxygen. This process is called “aerobic glycolysis” or “Warburg effect”. PFK-phosphofructokinase; ATP-adenosine triphosphate; ADP-adenosine diphosphate; ROS-reactive oxygen species. Adapted from SMART Servier Medical Art image bank (SMART, 2020SMART. [homepage on the Internet] Lyon, France: Servier Medical Art; 2020 [cited 2020 Jul 02]. Available from: https://smart.servier.com/.
https://smart.servier.com/... ).

Thumbnail

Figure 2
During the pre-implantation development of bovine embryos, the paternal and maternal genome are reprogrammed after fertilization. During this period, the maternal stock of mRNAs is consumed until the embryo is capable of producing its set of transcripts, a critical step known as the major embryonic genome activation. Up to this point, most of the epigenetic marks that were present during the first cleavages were substantially erased (5mC, H3K9ac, H3K18ac, H3K9me3, H3K27me3, H3K64me3, H4K20me3 and H3K4me3). After the major embryonic genome activation all epigenetic marks described for bovine embryos increase, even H4K5ac and H4K8ac that were observed in lower levels since zygote stage. The only exception is H3K9me2 that presents a unique pattern during throughout development. This reprogramming is how the developing embryo ‘writes’ its own profile of epigenetic marks.

Thumbnail

Figure 3
The folate cycle starts with the production of THF (tetrahydrofolate) from folate. THF is then converted into Methylene-THF and Methyl-THF, which is required for the production of methionine. The methionine can be converted to S-Adenosylmethionine (SAM) that acts as a methyl-group donor both DNA and histone methylation through the respective enzymes (DNMTs and HMTs). The consumption of the methyl group from SAM results in SAH (S-Adenosylhomocysteine), which can be converted to homocysteine and, again, to methionine. Glucose and pyruvate can produce acetyl-CoA, either by entering the mitochondria and being converted to citrate, or directly in the cytoplasm. Another source of Acetyl-CoA is the ß-oxidation of fatty acids. The acetyl-CoA generated can be used as an acetyl group-donor for histone acetylation by HATs (histone acetyl transferase enzymes). The removal of histone acetylation is promoted by HDAs enzymes and results in acetate production. Following in the tricarboxylic acid (TCA) cycle, the α-Ketoglutarate (α-KG) can be produced and transported to the cytosol and, later be used as substrate by TET or JmjC domains containing enzymes that promote, respectively, DNA and histone demethylation. Another source of α-KG are glutamine and glutamate. The α-KG that remains in the TCA cycle is converted to succinate. Succinate might continue in TCA cycle by and ultimately lead to the production of oxaloacetate. However, the succinate can leave the mitochondria and prevent DNA and histone demethylations by blocking TET or JmjC domain containing enzymes activity, respectively. At different steps of the tricarboxylic acid (TCA) cycle the consumption of NAD⁺ is necessary. NAD⁺ modulate sirtuin activity, a specific group of HAT. DNMT-DNA methyltransferase; HMT-histone methyltransferase; TET-ten-eleven translocation methylcytosine dioxygenase; HDAC-histone deacetylase, HAT-histone acetyltransferase. Adapted from SMART Servier Medical Art image bank (SMART, 2020SMART. [homepage on the Internet] Lyon, France: Servier Medical Art; 2020 [cited 2020 Jul 02]. Available from: https://smart.servier.com/.
https://smart.servier.com/... ).

Thumbnail

Figure 4
In vivo and in vitro environmental conditions are capable of influencing the phenotype both directly and indirectly. Indirectly, the environment may lead to changes in cell metabolism and affect the production of co-factors for epigenetic modifications. In this sense, the modifications of culture and production systems based on metabolic characteristics is a promising tool to improve embryo viability and animal production. SAM-S-adenosylmethionine. Adapted from SMART Servier Medical Art image bank (SMART, 2020SMART. [homepage on the Internet] Lyon, France: Servier Medical Art; 2020 [cited 2020 Jul 02]. Available from: https://smart.servier.com/.
https://smart.servier.com/... ).

Figure 1 Embryo development requires the activation of specific pathways to produce energy. Prior to compactation, embryo metabolism is mainly supported by pyruvate and amino acids, metabolized through tricarboxylic acid (TCA) cycle and oxidative phosphorylation. At the time of compactation, embryo increases its energetic demand especially for increasing biosynthesis and cell proliferation, but also for the formation and expansion of blastocoel, and hatching. At this time, glucose is metabolized with greater efficiency by two main pathways: the pentose phosphate pathway (PPP) (important for biomass and nucleotide generation) and the glycolytic pathway (that increases ATP production and pyruvate synthesis). At the end of the glycolytic pathway, pyruvate can also be converted to lactate, even in the presence of oxygen. This process is called “aerobic glycolysis” or “Warburg effect”. PFK-phosphofructokinase; ATP-adenosine triphosphate; ADP-adenosine diphosphate; ROS-reactive oxygen species. Adapted from SMART Servier Medical Art image bank (SMART, 2020SMART. [homepage on the Internet] Lyon, France: Servier Medical Art; 2020 [cited 2020 Jul 02]. Available from: https://smart.servier.com/.
https://smart.servier.com/... ).

Figure 2 During the pre-implantation development of bovine embryos, the paternal and maternal genome are reprogrammed after fertilization. During this period, the maternal stock of mRNAs is consumed until the embryo is capable of producing its set of transcripts, a critical step known as the major embryonic genome activation. Up to this point, most of the epigenetic marks that were present during the first cleavages were substantially erased (5mC, H3K9ac, H3K18ac, H3K9me3, H3K27me3, H3K64me3, H4K20me3 and H3K4me3). After the major embryonic genome activation all epigenetic marks described for bovine embryos increase, even H4K5ac and H4K8ac that were observed in lower levels since zygote stage. The only exception is H3K9me2 that presents a unique pattern during throughout development. This reprogramming is how the developing embryo ‘writes’ its own profile of epigenetic marks.

Figure 3 The folate cycle starts with the production of THF (tetrahydrofolate) from folate. THF is then converted into Methylene-THF and Methyl-THF, which is required for the production of methionine. The methionine can be converted to S-Adenosylmethionine (SAM) that acts as a methyl-group donor both DNA and histone methylation through the respective enzymes (DNMTs and HMTs). The consumption of the methyl group from SAM results in SAH (S-Adenosylhomocysteine), which can be converted to homocysteine and, again, to methionine. Glucose and pyruvate can produce acetyl-CoA, either by entering the mitochondria and being converted to citrate, or directly in the cytoplasm. Another source of Acetyl-CoA is the ß-oxidation of fatty acids. The acetyl-CoA generated can be used as an acetyl group-donor for histone acetylation by HATs (histone acetyl transferase enzymes). The removal of histone acetylation is promoted by HDAs enzymes and results in acetate production. Following in the tricarboxylic acid (TCA) cycle, the α-Ketoglutarate (α-KG) can be produced and transported to the cytosol and, later be used as substrate by TET or JmjC domains containing enzymes that promote, respectively, DNA and histone demethylation. Another source of α-KG are glutamine and glutamate. The α-KG that remains in the TCA cycle is converted to succinate. Succinate might continue in TCA cycle by and ultimately lead to the production of oxaloacetate. However, the succinate can leave the mitochondria and prevent DNA and histone demethylations by blocking TET or JmjC domain containing enzymes activity, respectively. At different steps of the tricarboxylic acid (TCA) cycle the consumption of NAD⁺ is necessary. NAD⁺ modulate sirtuin activity, a specific group of HAT. DNMT-DNA methyltransferase; HMT-histone methyltransferase; TET-ten-eleven translocation methylcytosine dioxygenase; HDAC-histone deacetylase, HAT-histone acetyltransferase. Adapted from SMART Servier Medical Art image bank (SMART, 2020SMART. [homepage on the Internet] Lyon, France: Servier Medical Art; 2020 [cited 2020 Jul 02]. Available from: https://smart.servier.com/.
https://smart.servier.com/... ).

Figure 4 In vivo and in vitro environmental conditions are capable of influencing the phenotype both directly and indirectly. Indirectly, the environment may lead to changes in cell metabolism and affect the production of co-factors for epigenetic modifications. In this sense, the modifications of culture and production systems based on metabolic characteristics is a promising tool to improve embryo viability and animal production. SAM-S-adenosylmethionine. Adapted from SMART Servier Medical Art image bank (SMART, 2020SMART. [homepage on the Internet] Lyon, France: Servier Medical Art; 2020 [cited 2020 Jul 02]. Available from: https://smart.servier.com/.
https://smart.servier.com/... ).

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Erasing gametes to write blastocysts: metabolism as the new player in epigenetic reprogramming

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[1] *Corresponding author: marcella.milazzotto@ufabc.edu.br