Consequences of assisted reproductive techniques on the embryonic epigenome in cattle
Rocío Melissa RiveraDivision of Animal Science University of Missouri, Columbia, Missouri 65211, USA. Email: riverarm@missouri.edu
Reproduction, Fertility and Development 32(2) 65-81 https://doi.org/10.1071/RD19276
Published: 2 December 2019
Journal Compilation © IETS 2020 Open Access CC BY-NC-ND
Abstract
Procedures used in assisted reproduction have been under constant scrutiny since their inception with the goal of improving the number and quality of embryos produced. However, in vitro production of embryos is not without complications because many fertilised oocytes fail to become blastocysts, and even those that do often differ in the genetic output compared with their in vivo counterparts. Thus only a portion of those transferred complete normal fetal development. An unwanted consequence of bovine assisted reproductive technology (ART) is the induction of a syndrome characterised by fetal overgrowth and placental abnormalities, namely large offspring syndrome; a condition associated with inappropriate control of the epigenome. Epigenetics is the study of chromatin and its effects on genetic output. Establishment and maintenance of epigenetic marks during gametogenesis and embryogenesis is imperative for the maintenance of cell identity and function. ARTs are implemented during times of vast epigenetic reprogramming; as a result, many studies have identified ART-induced deviations in epigenetic regulation in mammalian gametes and embryos. This review describes the various layers of epigenetic regulation and discusses findings pertaining to the effects of ART on the epigenome of bovine gametes and the preimplantation embryo.
Additional keywords: DNA methylation, epigenetics, histones, in vitro production of embryos, large offspring syndrome.
Introduction
The first successful transfer of an in vivo-produced bovine embryo dates back to 1951 (Willett et al. 1951). By the 1970s, assisted reproductive techniques (ARTs) had already started to be used in domestic animals, but IVF was not achieved in cattle until the early 1980s (Brackett et al. 1982) and it would be another decade before the first ART calves (produced by IVM, IVF and in vitro culture) were born (Fukuda et al. 1990). ART procedures have been under constant scrutiny since their inception with the common goal of improving the number and quality of embryos produced (Luvoni et al. 1996; Sugimura et al. 2017). Although most reports use specific stages of preimplantation development as the end point to determine the adequacy of the embryo, especially compared with in vivo-produced counterparts, the ultimate goal of an in vitro system for many is the production of a live and healthy calf with improved genetic potential (Hasler 2014; Sirard 2018). Presently, approximately 900 000 embryos are transferred worldwide each year, with two-thirds of those transfers occurring in South America, primarily in Brazil.
The in vitro production of embryos is not without complications. Many fertilised oocytes do not reach the blastocyst stage, and even those that develop to this stage do not always mimic the physiology of their in vivo counterparts. Further, only a portion of those destined to be transferred complete normal fetal development. A severe and unwanted consequence of the production of bovine embryos in vitro is the induction of a syndrome characterised by fetal overgrowth and structural malformations, as well as placental abnormalities (Farin and Farin 1995; Sinclair et al. 1999; Chen et al. 2013). The syndrome, referred to as large offspring syndrome (LOS) or abnormal offspring syndrome (AOS), has been associated with inappropriate control of the epigenome, especially of imprinted genes (Young et al. 2001; Farin et al. 2010; Chen et al. 2015).
Epigenetics, literally meaning ‘above genetics’, refers to the study of covalent and non-covalent modifications of DNA and histone proteins, as well as the mechanisms by which such modifications affect overall chromatin structure and function. Further, an extended definition of ‘epigenetics’ often includes the study of mechanisms involved in the post-transcriptional regulation of genes, such as regulation of transcript abundance by non-coding RNAs and RNA editing. Establishment and maintenance of epigenetic marks during gametogenesis and early embryogenesis play essential roles in preservation of DNA integrity and stability, cell lineage specification, X chromosome inactivation (in female embryos) and monoallelic expression of imprinted genes. Together, these layers of DNA control and regulation are responsible for the maintenance of cell identity and function by faithfully controlling inheritance of cell-specific chromatin states and associated gene expression patterns.
ARTs (i.e. superovulation, IVM of oocytes, IVF, embryo culture and embryo transfer) are implemented in cells and organisms undergoing vast epigenetic reprogramming of the genome (e.g. protamine–histone exchange, DNA demethylation (active and passive) and remethylation) and rapid mitosis and cell differentiation (Nakazawa et al. 2002; MacDonald and Mann 2014). Because the epigenome is responsive to the environment, it is not surprising that embryos produced in vitro have altered gene expression and concomitant changes in chromatin states compared with similar age or stage in vivo-produced embryos. As a result, studies comparing in vivo- and in vitro-produced embryos often conclude that these differences indicate errors in the developmental program of the embryo. This altered state of genetic output may be nothing more than the response of an organism (i.e. embryo) as it adapts to its environment. The problem occurs when this embryo is taken from the environment to which it has adapted, and in which it thrived, and transferred to a much different environment, namely the uterus, and expected to behave ‘normally’.
When an embryo develops in vitro, it experiences constant manipulations, changes in pH, high oxygen tension, exposure to light, osmolality differences, embryonic waste and break down of medium components, a stiff culture substrate, temperature changes and exposure to various culture media components, some of which are undefined and inconsistent (i.e. serum, bovine serum albumin (BSA)), among other insults. Further, the embryo that develops in vitro often forms from an oocyte that was induced to mature (and, often, rescued from apoptosis) under suboptimal conditions and in the presence of exogenous hormone stimulation. Thus, the oocyte from which an in vitro-produced embryo is formed is also likely to be aberrantly programmed epigenetically.
The study of the epigenome in mammalian oocytes and preimplantation embryos is complicated as a result of the paucity of cells available for analyses. Most of the work that has been done using these cell types has necessitated pooling of material in order to reach assay thresholds for the evaluation of treatment effects. An issue when using pools of embryos for epigenetic analyses is the fact that male and female embryos have different gene expression patterns (Bermejo-Alvarez et al. 2011) and thus different epigenetic programs (Dobbs et al. 2014), and experimental designs do not always account for this confounding. Our ability to understand the epigenome of preimplantation stage embryos is further complicated because every cell type has its own epigenetic program (Guo et al. 2014; Luo et al. 2018). For example, at the blastocyst stage of development, a bovine embryo possesses at least three cell types (i.e. epiblast, hypoblast and trophectoderm), each with its own epigenetic program that was acquired as a result of factors driving its specification and differentiation (Negrón-Perez et al. 2017). Therefore, by pooling material for analyses, we are making conclusions on averages, sometimes of multiple cell types, rather than determining absolute cellular states. To circumvent the limitation of number of cells and varied epigenetic programs, investigators are turning to new technologies that allow the amplification of single-cell transcriptomes and epigenomes (Kunowska 2019). These technologies, although very promising, currently require multiple rounds of amplifications, a step that is known to introduce bias to the results (Stegle et al. 2015).
Regardless of the aforementioned limitations and confoundings, it is important to acknowledge and appreciate how environment can affect the various layers of epigenetic regulation in bovine gametes and embryos. This understanding will invariably help researchers identify epigenetic signatures (and the conditions that promote them) that are correlated with successful development to term, even if dissimilar to their in vivo counterparts.
This review gives a brief description of the various layers of the epigenome and discusses ART-related findings on the epigenome, with special emphasis on results pertaining to DNA methylation. For the purpose of this review, the discussion is focused on research performed using non-invasive in vitro procedures. In particular, a discussion of somatic cell nuclear transfer will be excluded because this procedure involves somatic cell epigenetic reprogramming and it is not easy to unravel the relative contribution of somatic cell reprogramming (or lack thereof) from effects of the in vitro environment on the epigenetic program of preimplantation stage embryos.
DNA methylation
The transfer of the methyl group (CH3) from S-adenosyl-l-methionine (SAMe) to the fifth carbon of cytosine on DNA by DNA methyltransferases (DNMTs) is referred to as DNA methylation (Kalousek and Morris 1969). In mammals, DNA methylation occurs primarily in a cytosine–guanine (CpG) context (where ‘p’ refers to the phosphodiester bond between the bases; Ziller et al. 2011). DNA methylation is an epigenetic modification that is inherited through cell division and controls gene expression; usually in a repressive manner when present in promoter regions and transcription start sites (Jones 2012). DNA methylation is critical for development and reprogramming of the embryo (Okano et al. 1999), repression of retrotransposons (Walsh et al. 1998), genomic imprinting (DeBaun et al. 2003; Ideraabdullah et al. 2008), gene expression (Nagae et al. 2011) and X chromosome inactivation (Riggs 1975; Cotton et al. 2011).
DNA methylation is established and maintained by DNMTs (Edwards et al. 2017). DNMT3A and DNMT3B are the de novo DNMTs and, together with their non-catalytic partner DNMT3L, are responsible for establishing DNA methylation patterns during early germ cell development and remethylation of the preimplantation genome (Okano et al. 1999; Smallwood and Kelsey 2012). DNMT1, the maintenance methyltransferase, primarily acts on hemimethylated DNA (Takeshita et al. 2011) and is crucial for mammalian embryo development (Hirasawa et al. 2008). DNMT1 interacts with proliferating cell nuclear antigen (PCNA) at the replication fork to copy the methylation pattern to the newly synthesised daughter strand (Chuang et al. 1997; Fatemi et al. 2001; Hermann et al. 2004; Bostick et al. 2007; Sharif et al. 2007). In addition, DNMT1 interacts with ubiquitin like with PHD and ring finger domains 1 (UHRF1), which identifies hemimethylated DNA and ubiquitinates DNMT1 in order to promote its methyltransferase activity (Qian et al. 2008). Methylated cytosines promote a silent state of genes by attracting methyl-CpG-binding domain (MBD) proteins that form large protein complexes that have chromatin-modifying capabilities and prevent binding of transcriptional regulators (Wakefield et al. 1999; Fujita et al. 2000; Ohki et al. 2001; Zou et al. 2012).
Up to 70% of CpG sites are methylated in the mammalian genome (Strichman-Almashanu et al. 2002; Illingworth et al. 2010; Popp et al. 2010). CpG islands (CpGI), defined as being longer than 500 bp (~1–4 kb) and having a GC content >50% and an observed : expected CpG ratio of 0.65, generally lack DNA methylation (Takai and Jones 2002; Yamada et al. 2004; Smallwood et al. 2011; Jones 2012; Messerschmidt et al. 2014). CpGI are associated with the promoter region of genes, but they are also found in exons, introns and repetitive elements (Robertson 2005; Jones 2012). Promoter regions of ubiquitously expressed housekeeping genes are generally hypomethylated (CpGs in question are unmethylated; Beatty et al. 2006), whereas tissue- or developmental stage-specific promoters are hypermethylated (CpGs in question are methylated) in tissues that do not express the gene (Luo et al. 2018). Hypermethylated promoters are associated with silent genes, but because most CpGI (~60% of promoters; Illingworth et al. 2010) are hypomethylated, it is often difficult to associate regulation of gene expression with levels of DNA methylation (Chen et al. 2017). Gene expression is regulated by the association of promoters and enhancers (Allen and Taatjes 2015) and DNA methylation at enhancers can often help explain patterns of gene expression (Almamun et al. 2014).
The mammalian genome undergoes two rounds of global demethylation. The first occurs in primordial germ cells (PGC) and the second occurs after fertilisation and during preimplantation development (Hajkova et al. 2010; Dobbs et al. 2013; Hackett et al. 2013; Jiang et al. 2018). Specific for the bovine embryo, DNA demethylation declines after fertilisation, reaching a nadir at the 8-cell stage (Dobbs et al. 2013; Jiang et al. 2018). Both rounds of DNA demethylation involve the enzymatic activity of the ten–eleven translocation (TET) DNA methylcytosine dioxygenase, as well as the downregulation or removal of enzymes involved in DNA methylation (Hackett et al. 2013). TET family enzymes can oxidise 5-methylcytosine (5-meC) to form 5-hydroxymethylcytosine (5-hmeC), which can be passively removed through DNA replication or actively reverted to cytosine through iterative oxidation reactions to 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC), followed by replication-dependent dilution or thymine DNA glycosylase (TDG)-mediated base excision repair (Kohli and Zhang 2013; Wu and Zhang 2017). TDG-associated demethylation may not happen in bovine because the transcript is not detectable in embryos (Duan et al. 2019). The passive DNA demethylation in PGC affects the entire genome, although some repetitive DNA remains partially methylated (Hackett et al. 2013). Following fertilisation, both oocyte- and sperm-derived genomes undergo global DNA demethylation, but the demethylation mechanism is asymmetric between parental genomes (MacDonald and Mann 2014). DNA demethylation of the paternal genome occurs before DNA replication, indicating an active mechanism (MacDonald and Mann 2014), whereas the maternal genome primarily undergoes replication-dependent (passive) DNA demethylation (Howell et al. 2001; Inoue et al. 2011; Inoue and Zhang 2011).
Histone proteins
Histones are a family of basic proteins that, together with 146 bp of DNA, make up nucleosomes, the functional unit of chromatin (Luger et al. 1997). The canonical histones, namely H2A, H2B, H3 and H4, are synthesised and deposited during replication (Marzluff et al. 2008). Histones contain a positively charged N-terminal tail that can undergo post-translational modifications (HPTM) to affect the opening or compaction of chromatin (euchromatin vs heterochromatin respectively). More than 150 histone modifications have been reported, including acetylation, methylation, phosphorylation, ubiquitination, crotonylation and sumoylation (Zhao and Garcia 2015). Most of the research in which a treatment or physiological state seeks an epigenetic explanation via HPTM, analyses histone acetylation and methylation. Histone acetylation is associated with a permissive state of chromatin (euchromatin; Görisch et al. 2005). This modification is added to chromatin by various histone acetyltransferases (commonly referred to as coactivators) such as CREB-binding protein (CBP) and its homologue p300 (Bedford and Brindle 2012). Other modifications associated with active chromatin are the cotranscriptionally (Soares et al. 2017) added modifications such as lysine (K) 4 trimethylation (me3) on histone 3 (H3K4 me3) and H3K36 me3, which are enriched in the promoter and body of the gene respectively. Histone methylation also enriches regions of silent chromatin (heterochromatin). Heterochromatin exists in two states, namely facultative and constitutive heterochromatin (Trojer and Reinberg 2007; Saksouk et al. 2015). Facultative heterochromatin is decorated by H3K27 me3, a Polycomb complex-associated HPTM (Schwartz et al. 2006), or by H3K9 dimethylation (me2), a mark of the methyltransferase G9a (Scheer and Zaph 2017). Facultative heterochromatin includes regions of DNA that contain genes involved in developmental programming, such as the HOX genes (Bantignies and Cavalli 2011), and, through its contracting ability (Terranova et al. 2008), silences genetic domains such as imprinted genes (Terranova et al. 2008; see below) and the inactive X (Barr Body) in females (Zhao et al. 2008). Constitutive heterochromatin is enriched in H3K9 me3, a docking site for heterochromatin protein 1 (HP1), which facilitates apposition to the nuclear membrane (Nakayama et al. 2001; Poleshko et al. 2013). The HPTMs control gene expression by facilitating or preventing access to DNA through the interaction with factors and complexes that recognise the modifications. Beyond their post-translational modifications, histones also have variants that are deposited in a region- or cell cycle-specific manner. For example, histone H3.3 is enriched in areas of active transcription and in telomeres, centromere-specific H3 (CenH3) is enriched in centromeres, macro histone H2A is enriched in the silent allele of imprinted genes and in the inactive X chromosome, and H2ABb is associated with active chromatin (Blower et al. 2002; Valley et al. 2006; Campos and Reinberg 2009; Voon and Wong 2016; Buschbeck and Hake 2017). A very elegant report provides the most up-to-date catalogue of histone variants and modifiers in bovine oocytes and preimplantation stage embryos (Duan et al. 2019). That group captured transcripts for 14 histone variants, 52 histone methyltransferases, 29 histone demethylases 20 histone acetyltransferases, 19 histone deacetylases, four DNMTs and three DNA dioxygenases in eight stages of oocyte and embryo development.
Cross-talk between the various layers of epigenetic information is required for the acquisition of locus-specific epigenetic states. For example, MBD1 acts as a transcriptional repressor binding to methylated DNA. The repression is enhanced by the interaction of MBD1 with suppressor of variegation 3-9 homolog (SUV39H1; a H3K9 methyltransferase) and HP1 (Fujita et al. 2000). Further, MBD2 and MBD3 associate with the nucleosome remodeling deacetylase (NuRD) complex, which is comprised of chromatin remodelling ATPases and histone deactelyases (Clouaire and Stancheva 2008).
Genomic imprinting: inequivalent contribution of the parental genomes
In mammals, each somatic cell has two sets of chromosomes, one inherited from the mother through the oocyte and the other inherited from the father via the spermatozoon. Most genes in the resulting individual are expressed biallelically, meaning that both parental copies are transcribed. This would imply that as long as one copy of the gene is available, cellular homeostasis could occur and embryo and fetal development would be possible. However, studies in the 1980s with parental-specific chromosomal insufficiencies (e.g. uniparental disomies, deletions, single parental complement (parthenotes, androgenotes and gynogenotes)) demonstrated that both parental alleles are required for normal development of the conceptus (McGrath and Solter 1984; Surani et al. 1984). Further research in the early 1990s in mice showed that the parental inheritance of the aforementioned mutations rather than the mutation itself was what mattered for the well-being of the offspring. This was first demonstrated with three genes, namely insulin-like growth factor 2 receptor (Igf2r; Barlow et al. 1991), insulin-like growth factor 2 (Igf2; DeChiara et al. 1991) and H19 (Bartolomei et al. 1991). Original work identified the need of these newly discovered ‘imprinted genes’ as necessary for normal growth and development of the placenta and fetus, with deviations in fetal and placental size being main phenotypes (Coan et al. 2005) when these genes were incorrectly expressed (biallelically expressed or biallelically silent), a phenomenon known as loss of imprinting.
Genomic imprinting is then defined as a series of precisely regulated epigenetic processes that lead to parental allele-specific expression of a subset of genes in mammals (Bartolomei and Ferguson-Smith 2011). Proper allelic expression of imprinted genes plays an important role in embryo and neonatal growth, placental function and postnatal behaviour (Miyoshi et al. 2006). Allele-specific DNA methylation at discrete genomic regions known as imprinting control regions (ICR) is established during gametogenesis and defines the functional asymmetry of parental alleles (Bartolomei and Ferguson-Smith 2011). Hence, ICRs are regions of differential DNA methylation (i.e. differently methylated regions (DMR)). Imprinted genes occur in clusters through the genome (Verona et al. 2003). These clusters contain maternally expressed (paternally imprinted) and paternally expressed (maternally imprinted) genes and may also contain non-imprinted genes. The correct allelic expression of the imprinted genes within a cluster is orchestrated by the cluster’s ICR. However, not all imprinted DMRs are ICRs. ICRs are established during gametogenesis and, as such, are known as gametic DMRs or primary DMRs (John and Lefebvre 2011). Imprinted DMRs acquired after fertilisation are known as secondary DMRs or somatic DMRs (John and Lefebvre 2011). Imprinted DMRs are erased in primordial germ cells similar to the rest of the methylation epigenome, but they are protected during the DNA demethylation which occurs during preimplantation development (Bartolomei and Ferguson-Smith 2011). In addition to DNA methylation, HPTM, histone variants, MBDs, insulators/CCCTC-binding factor (CTCF) and non-coding (nc) RNAs contribute to parental allele-specific expression of these genes (Engel et al. 2006; Reese et al. 2007; Terranova et al. 2008; Gamble and Kraus 2010; Bartolomei and Ferguson-Smith 2011).
MicroRNA
The microRNAs (miRNAs) are small ncRNAs ~22 nucleotides in length with important roles in post-transcriptional gene regulation through targeting long RNAs for degradation or storage (Hutvágner and Zamore 2002; Seggerson et al. 2002; Doench and Sharp 2004; Bartel 2009). Mature miRNAs are processed from precursor miRNAs (pre-miRNAs), which, in turn, are processed from primary miRNAs (pri-miRNAs; Lee et al. 2002). The miRNA genes are located throughout the genome and can be found in exonic, intronic or intergenic regions (Lau et al. 2001).
Genes encoding miRNAs are transcribed in the nucleus by RNA polymerase II (Lee et al. 2004; Borchert et al. 2006) and may contain multiple miRNAs that are clustered together (Lee et al. 2002; Marsico et al. 2013). Like protein-coding genes, some miRNA genes have a transcription start site (TSS) and a termination site, and are accompanied by upstream regulatory elements like promoters, transcription factor binding sites and CpGI (Lee et al. 2004; Monteys et al. 2010). After transcription, pre-miRNAs are recognised and cleaved by the microprocessor complex, which consists of the RNase III enzyme DROSHA and the double-stranded RNA binding domain containing protein DiGeorge syndrome critical region gene 8 (DGCR8) (Lee et al. 2003; Gregory et al. 2004; Han et al. 2004). After cleavage, pre-miRNAs are bound by the protein exportin 5 (XPO5) in the presence of the cofactor RAS-related nuclear protein-guanosine-5′-triphosphate (Ran-GTP) and are transported to the cytoplasm through the nuclear pore complex (Yi et al. 2003). Once in the cytoplasm, pre-miRNAs interact with the RNA-induced silencing complex (RISC) loading complex, yielding a miRNA duplex of 21–23 bp (Hutvágner et al. 2001; Chendrimada et al. 2005). The RISC loading complex consists of DICER1 (an RNase III), TAR RNA binding protein 2 (TARBP2) and Argonaute 2 (AGO2), the catalytic component of the RISC complex (Meister et al. 2004).
In a mature miRNA sequence, the region encompassing the two to seven nucleotides from the 5′ end, defined as the ‘seed’ region, is critical for recognition of the target RNA. The level of complementarity between the miRNA and its target RNA determines whether the RNA will be degraded or prevented from undergoing translation. Studies have shown that near-perfect or perfect complementarity results in degradation, although emerging evidence suggest that miRNAs with imperfect complementarity can also cause mRNA decay in animals (Hendrickson et al. 2009). Translational repression is the result of a miRNA : mRNA complementarity that includes a mismatch, G : U wobble or bulge (Hutvágner and Zamore 2002; Seggerson et al. 2002; Doench and Sharp 2004). Translational regulation by miRNA can result from prevention of mRNA circularisation, polysome drop off (Pillai et al. 2005; Kiriakidou et al. 2007) and by promoting deadenylation of the target mRNAs (Giraldez et al. 2006; Wu et al. 2006).
Assisted reproduction and the epigenome
The ultimate goal of the use of ART in cattle is to improve the genetic merit of offspring in a shortened length of time compared with natural reproduction (Moore and Hasler 2017). Genetic merit is defined as the rank of an animal for its ability to produce superior offspring relative to other selection candidates (Purdue Extension 2003). In addition, ART can be used to produce genetically manipulated animals with improved production traits (Institute of Medicine and National Research Council 2004). However, as John F. Hasler (2014) has stated, ‘The issue of abnormal pregnancies involving in vitro embryos has not been satisfactorily resolved and the involvement of abnormal epigenetics associates with this technology merits continued research’.
The potential of the embryo to become a healthy calf is highly associated with the developmental competence of the oocyte, and it is important to understand how ART can alter the oocyte’s epigenome, because this is the epigenetic state that the embryo will use to complete its program. A short mention of the epigenome of spermatozoa is also included because it is now quite clear that the epigenetic information brought in by the semen/spermatozoon has vast consequences to the well-being of the embryo (Gòdia et al. 2018).
The oocyte
A female calf is born with approximately 133 000 primordial follicles (Erickson 1966). Oocytes within these follicles remain dormant in prophase of meiosis I until recruited to the growing follicle pool. The bovine oestrous cycle is a dynamic process and follicles are recruited in pools and grow together in two or three waves per cycle (Ginther et al. 1989; Muth-Spurlock et al. 2017). Oocyte growth and maturation occurs concomitant with follicle growth and is regulated by intraovarian oocyte–granulosa–theca cell interactions, as well as by autocrine and paracrine molecules such as steroids, growth factors and cytokines (Palma et al. 2012). However, less than 1% of a female’s primordial follicles will become ovulatory follicles (Erickson 1966). During each wave, one follicle will become a dominant follicle and only one of the dominant follicles will ovulate per cycle while the rest of the follicle–oocyte complexes will undergo apoptosis.
The oocyte’s ability to provide the appropriate genetic and epigenetic program for development to birth (i.e. developmental competence) is acquired during follicular growth. For example, Yang (1998) showed an increase of in vitro oocyte maturation and blastocyst formation when oocytes were collected from follicles 5–8 mm in diameter (84% and 52% respectively) compared with follicles 1–2 mm in diameter (58% and 26% respectively), indicating an incomplete developmental program in smaller follicles (Blondin and Sirard 1995; Ma et al. 2018). This is not surprising because oocytes resident in 1-mm follicles are only at ~70% (80 μm) of their final mature size of 120 μm. Bovine oocytes acquire the ability to resume meiosis at a diameter of ~100 μm, to reach the MII stage at a diameter of ~110 μm and to have full developmental competence at 120 μm (Fair et al. 1995, 1997; Otoi et al. 1997). The oocyte becomes transcriptionally inactive at a diameter of ~110 μm, at which time DNA methylation increases and nucleolus restructuration ensues as it continues to grow to the fully grown size of ~120 μm (Fair et al. 1995; O’Doherty et al. 2012).
Even though fertilisable, the oocytes nursed by the various dominant follicles do not have the same developmental potential. Muth-Spurlock et al. (2017) recently compared pregnancy rates in heifers impregnated during the first or second follicular wave and found a 46% increase in pregnancy rate (25.9% vs 72.0%) in females carrying offspring generated as a result of the second follicular wave; however this difference was not observed in cows (45.4% vs 50.0%). Procedures for ART in cattle often include a step of oocyte collection from ovaries (often heifers), either in vivo by superovulation and ovum pick-up (OPU) or ex-vivo after slaughter, in which case oocytes from antral follicles of various sizes are collected. Given that the majority of these follicles are destined for atresia and that the competence of the oocyte is dependent on the wave in which it develops, it is likely that the quality of most of oocytes used in bovine ART procedures is compromised. Although this is true to an extent, the oocyte’s program is resilient (Mermillod et al. 1999), as evidenced by the high rate of calves born in large-scale IVF programs (Pontes et al. 2010; Morotti et al. 2014). This fact indicates that the epigenome of the oocyte can quickly adapt to the new ‘artificial’ environment once liberated from the repressive physiological regulation of follicular demise.
DNA methylation is acquired in bovine oocytes during oocyte growth and is catalysed by DNMT3A, DNMT3B and DNMT3L (O’Doherty et al. 2012). Transcripts for several isoforms of DNMT1, namely DNMT1A and DNMT1B, are present in growing oocytes (Russell and Betts 2008; Rodriguez-Osorio et al. 2010). However, it is unlikely that this protein plays a major role in the remethylation event of the maternal genome because it has a cytoplasmic localisation in germinal vesicle stage oocytes (Lodde et al. 2009).
The environment an oocyte is exposed to during growth and maturation can affect the transcript and protein levels of the DNMTs. Maturation of oocytes in vitro, regardless of culture conditions used (TCM-199 in 20% oxygen or modified synthetic oviductal fluid in 5% oxygen) resulted in altered gene expression of DNMT1A, DNMT1B, DNMT3A and DNMT3B compared with oocytes matured in vivo (Heinzmann et al. 2011). In addition, treatment-specific effects have been observed for IVM oocytes. For example, Kahlon (2016) has shown that exposure to bisphenol A can decrease the total amount of DNMT1 protein in oocytes, whereas prolonged heat shock and melatonin increase transcript amount (Tian et al. 2014; Pavani et al. 2017). Further, work from Van Hoeck et al. (2011) identified increased levels of DNMT3A transcript in blastocyst stage embryos that developed from oocytes exposed to non-esterified fatty acids (NEFA) during IVM. This observation would suggest that oocyte maturation in the presence of high levels of NEFA transiently or permanently affect the (epi)genetic control of the DNMT3A gene that is not corrected during the global DNA demethylation event that occurs after fertilisation (Dobbs et al. 2014; Jiang et al. 2018).
In vitro culture conditions may cause an imbalance between oxidants and antioxidants to create a state of oxidative stress (Combelles et al. 2009) that can affect oocyte competence (Tamura et al. 2008). The antioxidant melatonin has been used to protect oocytes against damage by reactive oxygen species during IVM (Tamura et al. 2008; Tian et al. 2014; Zhao et al. 2018). However, it is not clear whether the effect is directly on the follicle or cumulus cells, the oocyte or both, because an inverse relationship has been observed between melatonin and intrafollicular concentrations of 8-hydroxy-2′-deoxyguanosine (8-OH-dG) in humans (Tamura et al. 2008). 8-OH-dG is one of the predominant forms of free radical-induced oxidative mutations (Valavanidis et al. 2009) and is widely used as a biomarker for oxidative stress. The 8-OH-dG adduct can induce loss of methylation of DNA when present at a CpG site by inhibiting the function of DNMT1 as the enzyme interacts with the guanine via its CXXC domain (Weitzman et al. 1994; Turk et al. 1995; Song et al. 2011). However, some research suggests that DNA methylation is not disturbed because of IVM (Heinzmann et al. 2011). In that study, the investigators compared DNA methylation at three imprinted ICRs between oocytes matured in TCM-199 in 20% oxygen or modified synthetic oviductal fluid in 5% oxygen and oocytes matured in vivo. The three regions chosen for study were H19, paternally expressed gene 3 (PEG3) and small nuclear ribonucleoprotein polypeptide N (SNRPN) DMRs. No deviations in DNA methylation were detected between treatments or between matured and immature oocytes. This observation may be specific for those DMRs because H19 is maternally unmethylated and the levels of DNA methylation are already high for SNRPN DMR in 110-µm oocytes (O’Doherty et al. 2012). In fact, a very recent study that used reduced representation bisulfite sequencing to query genome-wide CpGI methylation identified lower DNA methylation levels in IVM oocytes compared with their in vivo counterparts (Jiang et al. 2018).
Ovarian stimulation is used to increase the number of oocytes and embryos collected for experimentation, as well as to decrease the generation interval of genetically superior animals by producing embryos in genetically superior females and collecting them for fresh transfer or freezing. There are many superovulation schemes in bovine, but generally the procedure involves a series of twice daily injections of FSH (decreasing amounts) over 4–5 days beginning on Day 10 of the oestrous cycle (where Day 0 = oestrus). Day 10–11 is approximately the time of emergence of the second follicular wave; consequently, FSH administration results in selection of several dominant follicles instead of a single follicle. Three or four days after the initiation of the FSH injections, two injections of prostaglandin (PG) F2α are administered to initiate luteolysis. Oestrus normally occurs approximately 36–48 h after PGF2α administration (Kahn and Line 2010).
Some evidence indicates the potential for adverse developmental outcomes associated with the use of ovarian stimulation protocols in mammals. In rodents, ovarian stimulation increases the levels of postimplantation mortality, affects fetal growth, results in skeletal ossification and decreases the number of live fetuses (Beaumont and Smith 1975; Ertzeid and Storeng 1992, 2001; Van der Auwera and D’Hooghe 2001). In humans, studies have also shown negative effects relating to hormone stimulation. For example, chromosomally abnormal embryos were found to be more common following hormone stimulation (Van Blerkom and Henry 1992; Munne et al. 1997) and children born following superovulation and intrauterine insemination have an increased incidence of musculoskeletal defects (Olson et al. 2005) and poorer perinatal health (Klemetti et al. 2010). Collectively, these data demonstrate the negative effects on development and reproductive success associated with hormone stimulation procedures.
Although a multifactorial problem, superovulation has been shown to affect the epigenome in mammals (Market-Velker et al. 2010; Huffman et al. 2015). Because superovulation serves to stimulate the growth and ovulation of follicles and oocytes, this procedure is likely to have adverse effects on physiological and epigenetic processes in the oocyte. Indeed, we have shown this to be the case in the mouse (Almamun 2011; Huffman et al. 2015), where oocytes exposed to a superovulation scheme had reduced global immunoreactive 5-meC compared with oocytes developing in an unstimulated female (Almamun 2011). We also showed that the maternal pronucleus of zygotes recovered from females that had undergone a superovulation scheme had a 50% reduction in global levels of DNA methylation compared with zygotes from unstimulated females, which coincided with a 50% increase in H3K9/14 acetylation and with increased levels of gene expression of various epigenetic modifiers at the blastocyst stage (Huffman et al. 2015). This observation is in accordance with what has been found for Day 7 bovine embryos in which expression of the imprinted gene growth factor receptor-bound protein 10 (GRB10) was increased in in vitro-produced embryos when compared with in vivo-produced embryos that developed from completely unstimulated females (Mundim et al. 2009). Expression of this gene from the superovulated in vivo-produced group, although not statistically significant, showed an intermediate pattern between the two extremes. In addition, the sum of expression of three free radical scavengers (i.e. manganese superoxide dismutase, glutathione peroxidase 4 and catalase) tended to be greater in the in vitro-produced group than the naturally ovulated group, a finding relevant to the above discussion on the potential of DNA damage because of free radical formation during in vitro culture.
DNA methylation imprints are established in an oocyte size-specific manner in bovine (O’Doherty et al. 2012), a reaction catalysed by the de novo methyltransferases. Imprinted domains are not fully methylated in 110-µm oocytes (O’Doherty et al. 2012), which indicates that oocytes fertilised in vitro that have not yet reached their fully grown size may have inadequate maternal methylation imprints. This is of note because aberrant postnatal growth of bovine embryos produced in vitro has been associated with hypomethylation at potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) differentially methylated region (KvDMR1) and IGF2R ICRs, both of which are normally methylated on the maternal allele (Chen et al. 2017).
A way in which genetic potential may be expedited is by collecting oocytes or embryos from genetically superior prepubertal heifers (Moore and Hasler 2017). In a 2016 study, Landry et al. (2016) set out to determine the relationship between donor age and developmental competence during IVF. They found that young (5–10 months) Holstein females had a more pronounced response to FSH stimulation, as evidenced by a larger number of small (5–6 mm) and medium (7–10 mm) follicles, compared with postpubertal females aged 16–18 months. However, oocytes obtained from younger donors lacked full meiotic and/or developmental competence, demonstrated by a lower blastocyst rate (Landry et al. 2016), a phenomenon also observed by (Currin et al. 2017). Studies in ruminants are conflicting as to whether DNA methylation is different between pre- and postpubertal animals. Using limiting dilution bisulfite sequencing, Diederich et al. (2012) found that DNA methylation levels at repeat sequences were not different between groups, a finding also reported by Bernal-Ulloa et al. (2016) but in contrast with findings in the sheep, in which oocytes from young females had reduced levels of immuoreactive global DNA methylation (Ptak et al. 2006). More extensive work using next-generation sequencing would perhaps need to be done in order to identify whether there are specific loci that are not properly methylated in oocytes of prepubertal compared with adult females.
The sperm cell
Spermatozoa have the most highly compacted DNA in mammals (Ward and Coffey 1991). The compaction of DNA is the result of incorporation of protamines in the genome. Protamines are highly basic proteins (because of their high arginine and lysine content) that populate the paternal genome in the later stages of spermiogenesis and form disulfide bonds between cysteines (Ward and Coffey 1991; Balhorn et al. 1992; Dada et al. 2012; Hutchison et al. 2017). Chromatin compaction silences sperm genes, reduces the size of the sperm head for better hydrodynamic properties and protects DNA integrity during transport in the male and female reproductive tracts (Sillaste et al. 2017). The majority of DNA is packed with protamines forming a compact toroid structure (Brewer et al. 1999); however, between 1% and 15% (depending on species) of mature sperm DNA remains associated with histone proteins (Carrell and Hammoud 2010; Jung et al. 2017; Sillaste et al. 2017). After fertilisation, the paternal DNA undergoes a rapid protamine–histone exchange returning the paternal genome to a somatic chromatin configuration (i.e. nucleosome-containing chromatin;(Adenot et al. 1991). That is, when the protamines are removed from the paternal genome, maternal histones (inherited via the oocyte) are incorporated to once again form nucleosomes (McLay et al. 2002; Hatanaka et al. 2017). These histones are then post-translationally modified by maternally inherited epigenetic modifiers. The paternally inherited histones with their own HPTM convey paternal-specific genetic information to the early embryo. Regions of the male germline that resist the protamine exchange are enriched with active HPTM and flank genes and regulatory regions (i.e. enhancers) involved in early embryo development (Delaval et al. 2007; Jung et al. 2017). In addition, retained histones in spermatozoa safeguard imprinted domains on the paternal genome from the TET-induced global demethylation through binding of the maternal-effect gene developmental pluripotency associated protein 3 (DPPA3) to H3K9 me2 (Nakamura et al. 2012a).
HPTMs are associated with bull fertility. Studies have shown different levels of HPTM between high- and low-fertility bulls (Kutchy et al. 2018; Ugur et al. 2019). For example, H3K27ac and H3K27me3, modifications associated with enhancers and Polycomb silencing, respectively, are inversely correlated between high and low fertility bulls (Kutchy et al. 2018). Even though studies are lacking in bovine IVF, studies in humans suggest that the level of retention as well as the type of modifications present can affect fertility (La Spina et al. 2014).
There is a high content of small ncRNAs in semen, including miRNAs (Vojtech et al. 2014). Upon fertilisation, semen- or sperm-borne RNAs interact with the oocyte (Gòdia et al. 2018). Some of these ncRNAs act as epigenetic modifiers, inducing histone modifications and DNA methylation (Jodar et al. 2013). In addition, miRNAs (e.g. miR-34c) have roles in early embryo development (Boerke et al. 2007; Jodar et al. 2013). Bull fertility has been correlated with the small ncRNAs component of semen (Duan et al. 2019). In that study, the investigators identified 83 miRNAs and 79 potential PIWI-interacting RNAs (piRNAs; Dicer-independent small RNAs) dysregulated between high- and low-fertility bulls, with a large number of dysregulated miRNAs related to apoptosis. Another study reported that seven miRNAs (i.e. mir-502-5p, mir-1249, mir-320a, mir-34c-3p, mir-19b-3p, mir-27a-5p and mir-148b-3p) were differentially expressed between bulls of differing fertility (Fagerlind et al. 2015).
Preimplantation stage embryo
Upon fertilisation, the inherited parental epigenomes must transition from an epigenome corresponding to sex-specific germ cells to a somatic one. During this reprogramming event in mice, the imprinted gametic DMRs and some repetitive elements, such as intrascisternal A particle and centromeric repeats, retain their DNA methylation patterns during the wave of global DNA demethylation in early embryos (for a review, see Messerschmidt et al. 2014). In mouse zygotes (1-cell embryos), DPPA3 protects the maternal genome from TET3-mediated oxidation (i.e. formation of 5-hmeC; Nakamura et al. 2007, 2012b). DPPA3 distinguishes the maternal genome from the paternal genome by interacting with H3K9me2 (Nakamura et al. 2007), which is enriched in the maternal but not paternal gnome. DPPA3 is also required to maintain the allele-specific DNA methylation at several maternal gDMRs, such as PEG3 and PEG10, and paternal gDMRs such as H19/Igf2 and Rasgrf1 DMR (Nakamura et al. 2007) in mice. DPPA3 is abundant in the bovine oocyte (Thélie et al. 2007) and, similar to the case in the mouse, DPPA3 is required to maintain the maternal methylome by preventing the conversion of 5meC to 5hmeC (Bakhtari and Ross 2014). Knockdown of DPPA3 results in decreased cleavage rate and blastocyst formation, indicating the need for this maternal effect epigenetic reader for normal embryo development in the cow. Interestingly, IVM does not affect the transcript amount of DPPA3, because levels were similar between IVM embryos and their in vivo-matured counterparts (Thélie et al. 2007). However, whether the method of mammalian oocyte maturation affects protein amount remains to be elucidated.
During the first few cleavage divisions, the embryo’s epigenome must undergo epigenetic reprogramming to provide a chromatin state that will be appropriate for embryonic genome activation (EGA). In the cow, major EGA occurs at the 8- to 16-cell stage (Memili and First 1998) in in vitro-produced embryos and at the 4- to 8-cell stage in in vivo-produced embryos (Jiang et al. 2014), which means that epigenetic reprogramming is directed in early stage embryos by proteins and transcripts inherited via the gametes, primarily the oocyte. For example, lysine acetyltransferase 6B (KDM6B (jumonji domain-containing protein D3; JMJD3)); a histone acetyltransferase also known as MYST4) is an H3K27 me3 demethylase abundant in oocytes and decreases with each cleavage division, reaching a nadir at the 16-cell stage before increasing again by the blastocyst stage (Canovas et al. 2012). In the case of H3K9 me2, Lepikhov et al. (2008) have shown by immunofluorescent localisation that bovine and mouse zygotes have similar pronucleus-specific enrichment of this HPTM. KDM6B is required for early preimplantation development in bovine (Chung et al. 2017) because reducing the levels of maternal KDM6B mRNA by knockdown technology inhibited the reduction in global levels of H3K27me3 from 2- to 8-cell embryo stages and reduced development to the blastocyst stage. Chung et al. (2017) also detected a reduction in the number of inner cell mass and trophectoderm cells, as well as an altered transcriptome in the KDM6B-deficient embryos. An interesting observation from that work is that pathway analysis identified enrichment in categories such as chromosome organisation, chromatin configuration, chromatin organisation, chromatin remodelling and histone modification. Of note is that the epigenetic modifier SET domain bifurcated histone lysine methyltransferase 2 (SETDB2; (an H3K9 trimethyltransferase) was in four of the categories. SETDB2 is a member of the SUV39 family of heterochromatin-promoting lysine methyltransferases, which also includes SUV39H1, SUV39H2 and G9a (Wu et al. 2010), pointing to the need for an intact and undisturbed epigenome during the preimplantation stage for proper gene expression and timing of development. When comparing the transcript amount and patterns of all detectable epigenetic modifiers in bovine preimplantation embryos, Duan et al. (2019) found that transcript amount (protein arginine methyltransferase 5, PRMT5; lysine demethylase 5, KDM5B; lysine acetyltransferase 8, KAT8; histone deacetylase 1, HDAC1; histone deacetylase 8, HDAC8; H2A histone family member V, H2AFV; H2A histone family member Z, H2AFZ; histone acetyltransferase 1, HAT1; and TET methylcytosine dioxygenase 1, TET1), as well as timing of expression (H2AFV, H2AFZ, PRMT5, KDM5B, and HAT1), was altered in in vitro- compared with in vivo-produced embryos. In summary, embryos that are conceived by ART have altered expression of epigenetic modifiers, which results in inappropriate reprogramming of the epigenome, which translates into delayed EGA and reduced blastocyst potential.
A recent study compared the transcriptome of blastocyst stage embryos that developed from superovulated oocytes collected from young prepubertal Holstein female donors aged 8, 11 and 14 months (Morin-Doré et al. 2017). In that study, differences in gene expression for various epigenetic modifiers were detected between blastocysts from different groups. For example, when comparing embryos from female donors aged 8 and 11 months versus donors aged 14 months, Morin-Doré et al. (2017) identified an increased transcript amount for the enzyme acyl-CoA synthase short-chain family member 1 (ACSS1) in blastocysts from the younger groups. ACSS1 is involved in the conversion of acetate to acetyl-CoA, which, in turn, is an essential substrate for acetylation reactions in the cell, including histone acetylation (Golderer et al. 1987). A direct relationship between ACCS1 and increased histone acetylation (H3K9ac, H3K56ac and H3K27ac) in cancer cells has been identified (Gao et al. 2016). Further, Morin-Doré et al. (2017) found a reduced transcript amount of KAT6B, which was lower in the 8-month-old group than in the 14-month-old group. Other epigenetic modifiers with altered expression in that study were lysine methyltransferase 5B (KMT5B) and TET methylcytosine dioxygenase 3 (TET3), indicating that oocytes from young prepubertal females (at least those produced from a superovulation scheme) do not yet have the full capacity of directing proper control of the histones and DNA methylation at the blastocyst stage.
Long-term adverse consequences of ART in cattle
LOS is an overgrowth phenotype that has been observed in bovine and ovine fetuses and offspring that had been cultured during their preimplantation development (Young et al. 1998). LOS, also known as AOS (Farin et al. 2010), refers to a group of anomalous phenotypes sometimes observed in cattle and sheep conceptuses and newborns produced by ART. The first incidence of this syndrome dates back to the 1990s (Behboodi et al. 1995) and, since then, the syndrome has been reported and studied by many investigators (Behboodi et al. 1995; Farin and Farin 1995; Hasler et al. 1995; van Wagtendonk-de Leeuw et al. 2000; Lazzari et al. 2002; Chen et al. 2013, 2015, 2016, 2017; Li et al. 2019a, 2019b).
The increased body size can be detected as early as the fifth week of gestation in cattle (Hansen et al. 2016). Although enlarged body and limb size are prevalent phenotypes associated with this syndrome (Walker et al. 1996), LOS is not always characterised by overgrowth (Farin et al. 2006). Other phenotypes include large tongues, umbilical hernias, muscle and skeleton malformation, abnormal organ growth, allantois development defects, abnormal placental vasculature and even increased early embryo or fetus death rates (van Wagtendonk-de Leeuw et al. 1998; Farin et al. 2006). The large size of the offspring can result in dystocia and stillbirth (Takahashi et al. 2005), therefore affecting the dam and offspring and bringing financial loss to producers. Although the actual incidence of LOS in production systems is not known, two experimental accounts in ruminants suggest that approximately 25% of fetuses may develop into large-sized offspring (Carolan et al. 1995; Chen et al. 2015).
Supplement of serum during embryo culture has been historically used to stimulate blastocyst formation (Edwards 1965; Edwards et al. 1970). Adding serum and serum albumin during bovine embryo culture was found to improve and accelerate blastocyst yield by Day 6 (Carolan et al. 1995; Thompson et al. 1998) but decrease embryo survival rate. Serum can also result in increased organ size (Sinclair et al. 1999) and coculture of embryos with various types of cells (e.g. granulosa or oviduct epithelial cells) has been shown to increase blastocyst yield, induce overgrowth, alter myogenesis and increase gestation length (Kuzan and Wright 1982; Gandolfi and Moor 1987; Holm et al. 1996; Maxfield et al. 1997). Further, ruminant blastocysts that have been cultured with serum or somatic cells are darker in appearance due to excess lipid accumulation in the cytoplasm (Abe et al. 1999). In addition, these cultured embryos typically have fewer cells distributed to the inner cell mass and undergo cytoplasmic fragmentation.
Changes in imprinted and non-imprinted gene expression as a result of in vitro embryo production have been reported in numerous studies (Wrenzycki et al. 1999, 2001; Rizos et al. 2002, 2003; Gutiérrez-Adán et al. 2004; Corcoran et al. 2006; Fair et al. 2007; Giritharan et al. 2007; Jones et al. 2008; Katari et al. 2009; Smith et al. 2009; Driver et al. 2012; Chen et al. 2016, 2017). For example, different culture media and supplementation with serum caused changes in the transcript abundance of several developmentally important genes involved in cell–cell junctions, transport, RNA processing and stress in bovine embryos (Wrenzycki et al. 1999, 2001). As mentioned earlier, imprinted gene expression is associated with the growth and development of the conceptus and, as would follow, studies in various mammalian species have been conducted to identify whether embryo culture alters this epigenetic mechanism (Young et al. 2001; Rivera et al. 2008; Chen et al. 2013, 2015). Indeed, embryo culture can cause changes in DNA methylation and imprinted gene expression in mammals (Doherty et al. 2000), and this effect depends on the culture medium. A twofold increase in IGF2 RNA (a paternally expressed growth factor) has been reported in the liver of Day 70 bovine fetuses cultured in medium containing oestrus cow serum compared with the serum-restricted group (Blondin et al. 2000).
In our laboratory, we have been characterising the long-term effects of culture on gene expression and the epigenome of Day 105 bovine fetuses. We have observed global misregulation of imprinted (Chen et al. 2013) and non-imprinted transcripts in fetuses with LOS (Chen et al. 2017). In addition, we have identified aberrations in global DNA methylation in LOS fetuses (Chen et al. 2017), as well as global misregulation of miRNAs (Li et al. 2019b), and have shown misregulation of several imprinted miRNA clusters, including delta-like homologue 1 (DLK1)-iodothyronine deiodinase 3 (DIO3). This imprinted locus is referred to a ‘callipyge’; a genomic region associated with muscle development and hypertrophy. DNA hypermethylation was associated with downregulation of miRNAs in the DLK1-DIO3 cluster. When these datasets were analysed together, signalling pathways associated with control of organ size (including the HIPPO signalling pathway), cell proliferation, apoptosis, cell survival, cell cycle and cell adhesion were found to have aberrant expression in LOS. At present, we are undertaking careful molecular characterisation of LOS, including the identification of inappropriate expression of coding RNAs and ncRNAs, protein phosphorylation cascades, DNA methylation, genomic imprinting, tRNA halves and higher-order chromatin configuration, through preimplantation development and gestation in order to understand the multiple layers involved in the phenotypes known as LOS/AOS. In addition, we believe that this syndrome occurs naturally in cattle (i.e. in the absence of any ART procedure), a condition that we have coined spontaneous LOS (SLOS). We are currently characterising the epigenotype of SLOS to determine if it has the same epigenetic signature as ART-induced LOS (Li et al. 2019a).
Concluding remarks
It has been 30 years since the first calf completely produced in vitro was born (Fukuda et al. 1990). The use of ART has allowed rapid genetic improvement in cattle, which became more attractive to the industry after implementation of sexed spermatozoa to produce offspring (Viana et al. 2017). ART procedures in cattle normally start with a superovulation regime if in vivo collection is desired or by collecting oocytes from abattoir-harvested ovaries, which will require a period of IVM in order to achieve developmental competence. The matured oocytes are then fertilised and cultured in vitro for several days (~6–7 days) and then finally transferred to the uterus of a synchronised recipient. There are many deficiencies along the way and, on average, 20–40% blastocyst stage embryos are generally obtained, with the success rate being dependent on many factors, such as the maturity of the oocyte, in vitro conditions used (including media composition and oxygen tension) and technical expertise.
ART procedures are used at times of global epigenetic reprogramming in the oocyte and embryos (Bošković et al. 2012; MacDonald and Mann 2014). The mammalian oocyte acquires its epigenome during oocyte growth (Lucifero et al. 2004; Almamun 2011) and ART procedures, like superovulation and IVM, have been shown to affect it. After fertilisation, the genome of the preimplantation embryo undergoes another global epigenetic restructuration, one that has been shown by a large number of investigators in several mammalian species to be labile to ART manipulations and conditions. An extreme case of an altered epigenetic program caused by ART is the case of LOS (AOS), a condition that can have adverse effects on both the dam and offspring, not to mention financial loss to the producer.
Most studies in which ART procedures are tested show some level of epigenetic deviation from the gold standard in vivo-produced embryo, but it is hard to know how these deviations affect the true developmental program of the embryo because the work is often terminal (the endpoint is the blastocyst stage). To complicate matters, ART procedures are as varied as the laboratories and technicians performing them, and this fact makes it hard to dissociate the effects of one technique from another (because they need to be used in tandem), which prevents clarity of understanding of the effects of each on the epigenome. Further, although not discussed here, the genetic sequence can cause epigenetic differences (Chen et al. 2016), which may be a confounding factor if not accounted for. For example, methylated cytosines are prone to deamination and consequent C>T mutations (Cooper et al. 2010). If a specific CpG site is mutated to TpG, then it can no longer be methylated, which will change the epigenetic state of the locus. In addition, every cell type has its own epigenetic program and current single-cell technologies, although promising, are not perfect and require big data analysis knowledge and capabilities. Finally, yet another difficulty when studying the epigenome of an organism is that all layers of epigenetic regulation occur simultaneously, making it hard to conclude whether the epigenetic deviation being studied is a primary or secondary epimutation. Some time will pass before the field is capable of unmasking the complexities of the epigenome and how it is affected in its totality by ART. Nonetheless, by identifying specific deleterious epimutations, we can at least prevent the associated adverse outcomes to the offspring, dam and producer.
Conflicts of interest
The author declares no conflicts of interest.
Acknowledgements
Research from the author’s laboratory discussed in this review was supported by the National Institutes of Health (5R21HD062920), the National Science Foundation (1615789), Agriculture and Food Research Initiative Competitive Grant No. 2018-67015-27598 from the USDA National Institute of Food and Agriculture, the University of Missouri Research Board (RB 16-07 HAGEN) and the Food for the 21st Century Program Animal Reproduction Cluster at the University of Missouri.
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