Factors affecting early embryonic development in cattle: relevance for bovine cloning

Abstract

Female infertility represents a major challenge for improving the production efficiency in the dairy industry. Historically, fertility has declined whereas milk yield has increased tremendously due to intensive genetic selection. In vivo evidence reveals about 60% pregnancy loss takes place during the first month following fertilization. Meanwhile, early embryo development is significant for somatic cell nuclear transfer in cattle as a large proportion of cloned embryos fail to develop beyond peri-implantation stage. Oocyte quality is of utmost importance for the early embryo to develop to term for both fertilized and cloned embryos. Epigenetic reprogramming is a key process occurring after fertilization and critical roles of epigenetic modifiers during preimplantation development are now clear. Incomplete epigenetic reprogramming is believed to be a major limitation to cloning efficiency. Treatment of cloned embryos with epigenetic modifying drugs (e.g., Trichostatin A) could greatly improve cloning efficiency in both mice and cattle. Recently, the rapid progress in high-throughput sequencing technologies has enabled detailed deciphering of the molecular mechanisms underlying these events. The robust efficiency of genomic editing tools also presents an alternative approach to the functional annotation of genes critical to early development.

Keywords

bovine cloning / embryo development / somatic cell nuclear transfer / X-inactive specific transcript

1 Bovine embryo development

A calf’s life is initiated by the union of two highly differentiated gametes, an oocyte and a sperm (Fig. 1). During the first 2–3 weeks, the embryos are floating and migrating through the oviduct, entering the uterus, and elongating prior to attaching to the uterus endometrium for pregnancy establishment^[1]. Briefly following fertilization, the zygote cleaves several times and then moves to the uterus on day 4 after feritilization. As a unique mechanism, the majority of mRNA, proteins and energy substrates consumed in early embryos are derived from the maternal source (i.e., the oocyte) since RNA synthesis is globally silenced in the cleaved embryos until the embryo genome is activated primarily at the eight-cell stage in cattle^[2]. At the 16-cell stage, the embryo, usually called the morula, is polarized while blastomeres at this stage are difficult to distinguish under a regular stereo microscope^[3]. Compaction takes place at the 32-cell stage, which is much later than in mice^[4]. It has been believed that the outsides cells of a late morula would develop into the trophectoderm lineage and the inner cells migrate to one pole of the embryo to give rise to the inner cell mass lineage, which forms a special cavity-containing structure, namely the blastocyst^[5]. The blastocyst is formed shortly after the entry of early embryos into the uterus followed by hatching from the zona pellucida by day 9^[1].

Upon hatching, the spherical embryo grows rapidly in size and develops a tubular morphology before day 13. Considering the general similarity of development between fertilization and blastocyst stages among mammals, the early bovine embryo shows a characteristic of conceptus elongation^[1,6]. This elongation generally occurs exclusively in the trophoblast and the recognition of maternal pregnancy is via the production of a critical molecule, interferon tau (IFNT). Maximum production and secretion of IFNT by the trophoblast usually occurs between day 13 and 17, which eventually triggers the attachment of the embryo to the uterus endometrium 18–22 d after ovulation^[1,6].

Assisted reproduction technologies, including in vitro maturation (IVM) of oocytes and in vitro culture (IVC) of embryos, not only facilitate the study of fundamental developmental processes in early embryos but contribute extensively to infertility treatment, selective breeding and species conservation. Although the optimal requirements of oocytes and embryos in vitro have been intensively studied, the state of the art in vitro production system is still inferior to the normal in vivo environment of oocytes or embryos^[7,8]. An important limitation of in vitro manipulation of embryos may be the lack of optimal bidirectional communication between the mother and the embryo^[6]. In particular, improvements in vitro culture conditions for bovine embryos have been limited given the higher efficiency that has been achieved for mouse and human IVC. Moreover, although in vitro development of fertilized embryos can be extended to day 14 in humans^[9,10], it is usually only feasible to culture bovine embryos to blastocyst stage, and then only with a poor success rate (20%–50%)^[11–13].

As described above, early embryos grow in a short developmental window, however, with a series of dynamic morphological, molecular and developmental changes. These changes are sensitive to environmental, physiological and nutritional challenges, which may lead to early embryo death. The goal of the present review is to highlight the factors and challenges affecting early embryo development, and to discuss the potential options for improving reproductive efficiency in cattle. Emphasis is placed on dairy cattle and relevance to bovine cloning as early embryo loss is relatively frequent in this context.

Fig.1 Overview of early embryonic development in cattle and critical developmental events. Upon fertilization, the embryo cleaves three times in the oviduct before entering the uterus. Once the blastocyst forms, the embryo’s volume increases rapidly and the trophoblast elongates. Oocyte-derived molecules (e.g., mRNA and proteins) are the major drivers during initial development until the embryonic genome is activated at the eight-cell stage. The synthesis and secretion of IFNT from the elongated trophoblast is crucial for the maternal recognition of pregnancy. According to the statistics of Sartori et al.[14], the fertilization rate is high, however, the majority of pregnancy loss is observed during early embryonic development with 37% cleavage failure and 23% peri-implantation loss.

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2 Challenges in early embryo development in cattle

2.1 Early embryos loss in dairy cattle

In practice, early embryo loss during the first month after insemination has been a significant challenge in dairy cattle as it accounts for approximately 60% of total embryo/conceptus loss during pregnancy (Fig. 1), which is a major contributing factor that results in poor fertility in dairy cows^[15]. It has been observed that the calving rate is only 35%–40% after a single insemination in modern dairy cows and it is even lower in high yielding dairy cattle^[15–17]. To make things worse, over the last half century, the fertility of dairy cows has decreased as evidenced by the dramatic decline in fertility of dairy cattle populations in the USA and globally^{[14,15,18,19]}. In particular, daughter pregnancy rate, which refers to an estimate of the fertility of a bull’s daughter to become pregnant in a 21-day period, has decreased from over 30% in 1950s to about 24% today, according to USDA statistics^[1,19].

Accumulating evidence has indicated the time frame of early embryo loss. Fertilization seems normal for most cows as fertilization rates above 80% has been commonly observed in a range of independent studies^[14,15]. Growing evidence demonstrates 30-50% embryos are lost during the first week after insemination (Fig. 1), suggesting a critical role of development between fertilization and the blastocyst stage^[14,15,20]. The second peak time for embryo loss occurs during peri-implantation development (Fig. 1), i.e, concurrent with trophoblast elongation and the secretion of IFNT^[14,15].

2.2 Problems with early embryos produced by assisted reproduction technologies including somatic cell nuclear transfer

Numerous studies have shown that early embryos are vulnerable under in vitro culture conditions, which can lead to negative developmental outcomes, including early embryo death^[16,21]. These environmental impacts include uncharacterized additives (e.g., serum), temperature, humidity, light and embryo density. To illustrate, embryos grown in media containing serum have reduced viability^[22]. These embryos developed to day 14 after transfer and were 20% smaller than those produced from embryos cultured without serum or produced in vivo. Moreover, preimplantation embryos from ruminants are also vulnerable to environmental stressors.

Somatic cell nuclear transfer (SCNT) has been successfully used in a number of mammals for applications in animal breeding and therapeutic cloning. It appears that SCNT embryos have similar developmental potential to the blastocyst stage compared to that of in vitro fertilized (IVF) embryos^[23]. It is believed most embryos losses occur during the peri-implantation stage leading to pregnancy failure, although, fetal losses are also observed until late gestation^[23]. Consequently, the birth rate after embryo transfer is lower for SCNT than IVF. However, a plethora of aberrant phenotypes occur in the fetus and placenta for embryos generated by assisted reproduction, such as large offspring syndrome^[24,25].

These abnormal phenotypes may be due to the abnormal epigenetic reprogramming of the transferred somatic donor cell from a differentiated status to a totipotent state^[23,26,27]. Altered global DNA methylation has been observed in bovine SCNT embryos compared to IVF embryos and in vivo produced counterparts during preimplantation stages of development^[26–28]. Developmental events that are heavily regulated by epigenetic mechanisms including X chromosome inactivation and genomic imprinting are also impaired in bovine SCNT embryos^[29,30].

3 Factors influencing early embryo development

3.1 Genetic

Despite the low heritability for most fertility traits, accumulating evidence using state-of-the-art genome sequencing approaches has shown that reproductive functions are associated with various genomic loci or variations^[31,32]. For example, mutations in genes, including progesterone receptor^[33], FGF2^[34] and STAT5A^[35], are linked with embryonic developmental potential. According to data from the International Mouse Phenotyping Consortium, one quarter of all gene knockouts analyzed reveal themselves lethal and a large proportion of them are lethal to early embryos^[36]. Thanks to the advent of the genome selection approach, it is feasible to select elite cows by avoiding homozygous mutations that may cause early embryonic loss in cattle.

In vitro production of embryos presents an excellent model for delineating fundamental genetic control in early bovine embryos. Both high-throughput sequencing and candidate approaches have been used to identify putative critical genes for early embryos. By using siRNA-mediated silencing tool, we have discovered and characterized multiple genes, including Follistatin^[11], JY-1^[37], ZNFO^[38], CHD1^[39], H3F3A/H3F3B^[40], that are critical in early embryo development in cattle. Their special roles and potential mechanisms have been discussed in a recent review^[41].

3.2 Follicle and oocyte quality

During preimplantation development, particularly for the first couple of days after insemination, the embryos are substantially dependent on maternally stored factors derived from the oocyte^[41]. Oocyte quality, also termed oocyte competence, denotes the ability of an oocyte to complete meiosis, fertilization and cleavage, to proceed to early embryonic development, and eventually give rise to a healthy offspring^[42]. Currently, poor oocyte quality is one leading factors associated with reproductive failures in dairy cattle^[43]. It seems that oocyte quality could be disrupted by lactation in high yield dairy cattle, which may suggest there is a negative genetic correlation between fertility traits and milk yield traits^[31].

The acquisition of oocyte competence is primarily dependent on the environment of the follicle in which the oocyte resides^[44,45]. Indeed, a series of autocrine, paracrine (e.g., GDF9, BMP6 and FGFs) and endocrine (e.g., FSH, LH and estrogen) factors are pivotal in the growth and development of ovarian follicles, and thus impact oogenesis^[45–47]. These extra and intrafollicular molecules have been demonstrated as crucial components of a signaling network controlling ovarian follicle development^[48].

The role of progesterone in dairy cow fertility has received considerable attention^[49–51]. It has been claimed that a reduction of blood progesterone could be responsible for reduced fertility in dairy cows^[1]. The justification behind this hypothesis is that the metabolic activity is increased in the liver of high yielding dairy cattle and progesterone is subject to increased degradation. Administration of progesterone after insemination may improve fertility in dairy cattle^[49,52,53]. However, the specific role of progesterone in oocyte quality and early embryonic development is still debatable^[49].

Oocytes used as ooplasm recipients for SCNT are typically obtained from an abattoir, and the genetic background of these oocytes varies. Oocytes thus derived are matured in vitro under specific laboratory conditions. However, IVM conditions, including medium, air composition and PH, are still inferior relative to the in vivo conditions, which compromises the oocyte quality^[21,23,54]. Thus, it is common that the rate of development to the blastocyst stage is lower in in vitro matured oocytes used for SCNT than in in vivo matured oocytes^[55].

3.3 Epigenetic

Epigenesis was coined and defined by Conrad Waddington as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being”^[56]. More commonly, epigenetics is the study of heritable changes in gene function that are not the result of variation in DNA sequence. DNA methylation and histone modification are two the most intensively studied epigenetic modifications^[57].

DNA methylation: a type of post-replication covalent modification, which almost exclusively occurs in position 5 of cytosine, as well as CpG islands in mammals. By this modification, the chromatin is generally repressed, which therefore inhibits promoter activity^[58]. Moreover, this process is catalyzed by DNA methyltransferases using S-adnosylmethionine as the methyl donor. It was in 1975, Holliday and Pugh^[59] first proposed that DNA methylation might be involved in the maintenance of gene expression or chromatin structure. DNA methylation is now claimed to be vital for maintaining the stability of gene expression states, such as, X chromosome inactivation, gene imprinting and heterochromatin formation^[60].

Genome-wide demethylation of parental chromatin occurs following fertilization, with methylation reinitiated from the 16-cell stage onward in early bovine embryos^[61,62]. The mechanisms underlying the demethylation observed in early embryos have recently been identified^[61,63]. A novel DNA methylation form, 5-hydroxymethylcytosine, and its modifier Tet3 have been extensively shown to be critical for this demethylation process^[63,64]. Recent research has analyzed and mapped 5-methylcytosine and 5-hydroxymethylcytosine sites in early bovine embryonic stages^[65]. Detail of the progress can be found in recent reviews^[66–69].

Histone modification: Chromatin in eukaryotes characteristically shows extensive compaction whereby 2 m of DNA is packed into cells of about 20–30 mm in diameter^[70]. The compaction is used to protect genetic material and regulate DNA replication and RNA transcription. The basic unit of chromatin, the, nucleosome consists of 147 bp of DNA coiled around an octamer of histone proteins. The histone octamer consists of two copies of each histone protein (H2A, H2B, H3 and H4) with N-terminal tails protruding. Accumulating evidence indicates the core histones are subject to a growing list of more than 100 different post-translational modifications, including acetylation, methylation, ubiquitylation, phosphorylation and sumoylation^[70,71].

Upon fertilization, protamines enriched in sperm chromatin are replaced by canonical histones when dramatic histone modification occur^[66,72]. Studies in somatic cell lines determined that multiple histone modifications, such as histone H3 lysine 4, histone H3 lysine 36 and histone H3 lysine 79 methylation, are positively associated with gene activation, while the methylation of histone H3 lysine 9, histone H3 lysine 27 (H3K27) and histone H4 lysine 20 are generally involved in silencing gene expression^[70,73].

The specific roles of these histone modifications in early bovine embryonic development have only became apparent in recent years. H3K27 tri-methylation (H3K27me3) level appears dynamic in early bovine embryos with a sharp decline from the germinal vesicle to the eight-cell stage and an increase at the blastocyst stage, suggesting a critical role of H3K27me3 in early embryonic development^[74]. Further analysis revealed Jumonji domain-containing 3, an active component of polycomb repressive complex 2, is responsible for the removal of H3K27me3 during early bovine development^[75].

Aberrant epigenetic reprogramming, including DNA methylations and histone modifications, have been reported in SCNT embryos^[23] (Fig. 2). During the last decade, two milestones have been passed that laid a foundation for the dramatic improvement in developmental potential of cloned embryos. First, the treatment of cloned embryos with trichostatin A (TSA), a histone deacetylases inhibitor, which can significantly improve not only the blastocyst rate but also the full-term development success rate in mice^[76,77]. Similar beneficial effects have been observed in cattle^[78,79]. Second, transcriptomic analysis of cloned embryos has revealed that abnormal expression of certain histone modifiers is responsible for developmental failure of cloned embryos^[80,81]. However, it remains unclear if this phenotype also occurs in cattle. Furthermore, complete rescue of all the cloned embryos is not currently feasible with a large proportion of cloned embryos still failing to develop to term^[76,80,81].

Fig.2 Critical factors influencing bovine cloning efficiency. The oocyte provides ooplasm to reprogram the differentiated somatic cell to a totipotent state, suggesting a crucial role for oocyte quality in the development of cloned embryos. Oocyte quality is influenced by a variety of endogenous (genetic) and exogenous factors, including hormone milieu and heat shock. Incomplete epigenetic reprogramming is frequent in cloned embryos with aberrant DNA methylations and histone modifications. Xist, X-inactive specific transcript.

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3.4 Heat stress

In summer or after fever, a large reduction in female fertility in dairy cattle has been observed^[82]. In vitro evidence indicates that elevated temperature can directly affect embryos by reducing their viability (see reviews^[83–85]). Early embryos gradually acquire the capability of thermotolerance via balancing free radical production and antioxidant protection and apoptosis^[85]. Studies have shown that heat shock is detrimental to the developmental potential of zygotes and two-cell embryos, however, four- to eight-cell embryos are less sensitive and morulae are more resistant to heat shock.

The mechanisms by which embryos adjust to this stress have been studied, including altered hormone secretion, follicular development, steroid production and uterine blood flow^[85,86]. Similar to other cell types, embryos after heat shock undergo a series of biochemical responses induced by the high temperature. For example, heat shock protein 70 family proteins are the most notable molecules contributing to induced thermotolerance^[87]. In mice and cattle, the induced thermotolerance response has been observed in preimplantation embryos and is developmentally regulated^[88–90]. Accumulating evidence indicates mitochondria are prone to damage following heat shock with their main functions, including apoptosis and oxidative stress, being disrupted^[85].

3.5 Embryokines

Embryokines were first described by Hansen et al.^[95,91] as molecules produced and secreted by maternal reproductive tracts that are critical for the proper development of early embryos. A few embryokines produced by oviducts or the uterus have been identified and characterized^[92–94]. Thus, it is rational to believe that oocytes and embryos cultured in vitro are less competent than their in vivo counterparts due to the suboptimal conditions^[95,96]. To illustrate, one such molecule, colony stimulating factor 2 (CSF2), is synthesized and secreted by the oviduct and endometrium. Exposure of the early embryos to CSF2 can improve the pregnancy rate and birth rate, potentially through modulation of apoptosis and cell proliferations in ICM^[97,98]. The maternal age and metabolic status of the cow can affect the microenvironment of the reproductive tract. For example, the potential of embryos to develop to the blastocyst stage is reduced in postpartum lactating cows relative to nulliparous heifers^[99] and non-lactating cows^[100].

4 Conclusions and perspectives

4.1 Call for fundamental work in early bovine embryos

Understanding of the early embryonic development in mammals is far from complete, especially the molecular mechanisms governing critical developmental events, including epigenetic reprogramming, EGA, first lineage specification and implantation. Fundamental research in early mammalian embryos has usually been limited by scarcity of samples for molecular and biochemical assays. However, rapid progress in high-throughput analysis of genomic, transcriptomic and proteomic information with limited samples has greatly enhanced the capacity to dissect critical mechanisms of early embryonic development^[101,102].

Most information on the mechanisms of early development is derived from rodent models. Functional annotation of critical genes in early embryos of large animals is usually dependent on the use of molecular inhibitors, recombinant growth factors or siRNAs delivered by microinjection, but all these approaches have limitations. Recent progress in genomic editing tools [e.g., clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9)] will expand this toolkit and greatly enhance understanding of the fundamental principles of early bovine embryonic development.

4.2 Epigenetic solutions for improvement of SCNT efficiency

Certain chemicals, such as TSA, have dramatically improved SCNT efficiency, possibly by correction of epigenetic defects caused by SCNT^[76]. Manipulation of X chromosome-linked gene expression can also increase cloning efficiency^[30]. X-inactive specific transcript(Xist) knockdown in SCNT embryos can restore the genome-wide gene expression and increase cloning efficiency 10-fold^[30]. Xist expression is also upregulated in SCNT embryos of cattle^[29]. Further investigation of Xist knockdown in SCNT embryos might prove helpful for improving full-term development in cattle. Future study of the regulation of bovine epigenetic reprogramming in SCNT embryos is critical for providing novel insights required for developing drugs that may improve cloning efficiency.

References

[14] Sartori R, Bastos M R, Wiltbank M C. Factors affecting fertilisation and early embryo quality in single- and superovulated dairy cattle. Reproduction, Fertility, and Development, 2010, 22(1): 151–158

[1] Spencer T E. Early pregnancy: concepts, challenges, and potential solutions. Animal frontiers, 2013, 3(4): 48–55

[2] Graf A, Krebs S, Zakhartchenko V, Schwalb B, Blum H, Wolf E. Fine mapping of genome activation in bovine embryos by RNA sequencing. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(11): 4139–4144

[3] Koyama H, Suzuki H, Yang X, Jiang S, Foote R H. Analysis of polarity of bovine and rabbit embryos by scanning electron microscopy. Biology of Reproduction, 1994, 50(1): 163–170

[4] Van Soom A, Boerjan M L, Bols P E, Vanroose G, Lein A, Coryn M, de Kruif A. Timing of compaction and inner cell allocation in bovine embryos produced in vivo after superovulation. Biology of Reproduction, 1997, 57(5): 1041–1049

[5] Pfeffer P L, Pearton D J. Trophoblast development. Reproduction (Cambridge, England), 2012, 143(3): 231–246

[6] Sandra O, Charpigny G, Galio L, Hue I.Preattachment embryos of domestic animals: insights into development and paracrine secretions. Annual Review of Animal Biosciences,2017, 5: 205–228

[7] Hoshi H. In vitro production of bovine embryos and their application for embryo transfer. Theriogenology, 2003, 59(2): 675–685

[8] Hasler J F, Henderson W B, Hurtgen P J, Jin Z Q, Mccauley A D, Mower S A, Neely B, Shuey L S, Stokes J E, Trimmer S A. Production, freezing and transfer of bovine Ivf embryos and subsequent calving results. Theriogenology, 1995, 43(1): 141–152

[9] Deglincerti A, Croft G F, Pietila L N, Zernicka-Goetz M, Siggia E D, Brivanlou A H. Self-organization of the in vitro attached human embryo. Nature, 2016, 533(7602): 251–254

[10] Shahbazi M N, Jedrusik A, Vuoristo S, Recher G, Hupalowska A, Bolton V, Fogarty N N M, Campbell A, Devito L, Ilic D, Khalaf Y, Niakan K K, Fishel S, Zernicka-Goetz M. Self-organization of the human embryo in the absence of maternal tissues. Nature Cell Biology, 2016, 18(6): 700–708

[11] Zhang K, Rajput S K, Lee K B, Wang D, Huang J, Folger J K, Knott J G, Zhang J, Smith G W. Evidence supporting a role for SMAD2/3 in bovine early embryonic development: potential implications for embryotropic actions of follistatin. Biology of Reproduction, 2015, 93(4): 86

[12] Tribulo P, Leão B C D S, Lehloenya K C, Mingoti G Z, Hansen P J. Consequences of endogenous and exogenous WNT signaling for development of the preimplantation bovine embryo. Biology of Reproduction, 2017, 96(6): 1129–1141

[13] Rizos D, Clemente M, Bermejo-Alvarez P, de La Fuente J, Lonergan P, Gutierrez-Adan A. Consequences of in vitro culture conditions on embryo development and quality. Reproduction in Domestic Animals, 2008, 43(S4): 44–50

[15] Wiltbank M C, Baez G M, Garcia-Guerra A, Toledo M Z, Monteiro P L, Melo L F, Ochoa J C, Santos J E, Sartori R. Pivotal periods for pregnancy loss during the first trimester of gestation in lactating dairy cows. Theriogenology, 2016, 86(1): 239–253

[16] Lonergan P, Fair T, Forde N, Rizos D. Embryo development in dairy cattle. Theriogenology, 2016, 86(1): 270–277

[17] Liu A, Lund M S, Wang Y, Guo G, Dong G, Madsen P, Su G. Variance components and correlations of female fertility traits in Chinese Holstein population.Journal of Animal Science and Biotechnology, 2017, 8(56

[18] Lucy M C. Reproductive loss in high-producing dairy cattle: where will it end? Journal of Dairy Science, 2001, 84(6): 1277–1293

[19] Norman H D, Wright J R, Hubbard S M, Miller R H, Hutchison J L. Reproductive status of Holstein and Jersey cows in the United States. Journal of Dairy Science, 2009, 92(7): 3517–3528

[20] Diskin M G, Parr M H, Morris D G. Embryo death in cattle: an update. Reproduction, Fertility, and Development, 2011, 24(1): 244–251 doi:10.1071/RD11914

[21] Lonergan P, Fair T.Maturation of oocytes in vitro. Annual Review of Animal Biosciences, 2016, 4: 255–268

[22] Fernández-Gonzalez R, Moreira P, Bilbao A, Jiménez A, Pérez-Crespo M, Ramírez M A, Rodríguez De Fonseca F, Pintado B, Gutiérrez-Adán A. Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior. Proceedings of the National Academy of Sciences of the United States of America, 2004, 101(16): 5880–5885

[23] Akagi S, Matsukawa K, Takahashi S. Factors affecting the development of somatic cell nuclear transfer embryos in Cattle. Journal of Reproduction and Development, 2014, 60(5): 329–335

[24] Liu J, Wang Y, Su J, Luo Y, Quan F, Zhang Y. Nuclear donor cell lines considerably influence cloning efficiency and the incidence of large offspring syndrome in bovine somatic cell nuclear transfer. Reproduction in Domestic Animals, 2013, 48(4): 660–664

[25] Chen Z, Hagen D E, Elsik C G, Ji T, Morris C J, Moon L E, Rivera R M. Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(15): 4618–4623

[26] Kang Y K, Koo D B, Park J S, Choi Y H, Chung A S, Lee K K, Han Y M. Aberrant methylation of donor genome in cloned bovine embryos. Nature Genetics, 2001, 28(2): 173–177

[27] Santos F, Zakhartchenko V, Stojkovic M, Peters A, Jenuwein T, Wolf E, Reik W, Dean W. Epigenetic marking correlates with developmental potential in cloned bovine preimplantation embryos. Current Biology, 2003, 13(13): 1116–1121

[28] Dean W, Santos F, Stojkovic M, Zakhartchenko V, Walter J, Wolf E, Reik W. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proceedings of the National Academy of Sciences of the United States of America, 2001, 98(24): 13734–13738

[29] Xue F, Tian X C, Du F, Kubota C, Taneja M, Dinnyes A, Dai Y, Levine H, Pereira L V, Yang X. Aberrant patterns of X chromosome inactivation in bovine clones. Nature Genetics, 2002, 31(2): 216–220

[30] Inoue K, Kohda T, Sugimoto M, Sado T, Ogonuki N, Matoba S, Shiura H, Ikeda R, Mochida K, Fujii T, Sawai K, Otte A P, Tian X C, Yang X, Ishino F, Abe K, Ogura A. Impeding Xist expression from the active X chromosome improves mouse somatic cell nuclear transfer. Science, 2010, 330(6003): 496–499

[31] Berry D P, Friggens N C, Lucy M, Roche J R. Milk production and fertility in cattle. Annual Review of Animal Biosciences, 2016, 4: 269–290

[32] Kropp J, Peñagaricano F, Salih S M, Khatib H. Invited review: genetic contributions underlying the development of preimplantation bovine embryos. Journal of Dairy Science, 2014, 97(3): 1187–1201

[33] Driver A M, Huang W, Gajic S, Monson R L, Rosa G J M, Khatib H. Short communication: effects of the progesterone receptor variants on fertility traits in cattle. Journal of Dairy Science, 2009, 92(8): 4082–4085

[34] Khatib H, Maltecca C, Monson R L, Schutzkus V, Wang X, Rutledge J J. The fibroblast growth factor 2 gene is associated with embryonic mortality in cattle. Journal of Animal Science, 2008, 86(9): 2063–2067

[35] Khatib H, Monson R L, Schutzkus V, Kohl D M, Rosa G J M, Rutledge J J. Mutations in the STAT5A gene are associated with embryonic survival and milk composition in cattle. Journal of Dairy Science, 2008, 91(2): 784–793

[36] Dickinson M E, Flenniken A M, Ji X, Teboul L, Wong M D, White J K, Meehan T F, Weninger W J, Westerberg H, Adissu H, Baker C N, Bower L, Brown J M, Caddle L B, Chiani F, Clary D, Cleak J, Daly M J, Denegre J M, Doe B, Dolan M E, Edie S M, Fuchs H, Gailus-Durner V, Galli A, Gambadoro A, Gallegos J, Guo S, Horner N R, Hsu C W, Johnson S J, Kalaga S, Keith L C, Lanoue L, Lawson T N, Lek M, Mark M, Marschall S, Mason J, McElwee M L, Newbigging S, Nutter L M, Peterson K A, Ramirez-Solis R, Rowland D J, Ryder E, Samocha K E, Seavitt J R, Selloum M, Szoke-Kovacs Z, Tamura M, Trainor A G, Tudose I, Wakana S, Warren J, Wendling O, West D B, Wong L, Yoshiki A, MacArthur D G, Tocchini-Valentini G P, Gao X, Flicek P, Bradley A, Skarnes W C, Justice M J, Parkinson H E, Moore M, Wells S, Braun R E, Svenson K L, de Angelis M H, Herault Y, Mohun T, Mallon A M, Henkelman R M, Brown S D, Adams D J, Lloyd K C, McKerlie C, Beaudet A L, Bućan M, Murray S A. High-throughput discovery of novel developmental phenotypes. Nature, 2016, 537(7621): 508–514

[37] Lee K B, Wee G, Zhang K, Folger J K, Knott J G, Smith G W. Functional role of the bovine oocyte-specific protein JY-1 in meiotic maturation, cumulus expansion, and subsequent embryonic development. Biology of Reproduction, 2014, 90(3): 69

[38] Hand J M, Zhang K, Wang L, Koganti P P, Mastrantoni K, Rajput S K, Ashry M, Smith G W, Yao J. Discovery of a novel oocyte-specific Kruppel-associated box domain-containing zinc finger protein required for early embryogenesis in cattle. Mechanisms of Development, 2017, 144(Pt B): 103–112

[39] Zhang K, Rajput S K, Wang S, Folger J K, Knott J G, Smith G W. CHD1 regulates deposition of histone variant H3.3 during bovine early embryonic development. Biology of Reproduction, 2016, 94(6): 140

[40] Zhang K, Wang H, Rajput S K, Folger J K, Smith G W. Characterization of H3.3 and HIRA expression and function in bovine early embryos. Molecular Reproduction and Development, 2017, 85 (2):106–116

[41] Zhang K, Smith G W. Maternal control of early embryogenesis in mammals. Reproduction, Fertility, and Development, 2015, 27(6): 880–896

[42] Sirard M A, Richard F, Blondin P, Robert C. Contribution of the oocyte to embryo quality. Theriogenology, 2006, 65(1): 126–136

[43] Rispoli L A, Lawrence J L, Payton R R, Saxton A M, Schrock G E, Schrick F N, Middlebrooks B W, Dunlap J R, Parrish J J, Edwards J L. Disparate consequences of heat stress exposure during meiotic maturation: embryo development after chemical activation vs fertilization of bovine oocytes. Reproduction, 2011, 142(6): 831–843

[44] Santos J E, Bisinotto R S, Ribeiro E S. Mechanisms underlying reduced fertility in anovular dairy cows. Theriogenology, 2016, 86(1): 254–262

[45] Sirard M A. Somatic environment and germinal differentiation in antral follicle: the effect of FSH withdrawal and basal LH on oocyte competence acquisition in cattle. Theriogenology, 2016, 86(1): 54–61

[46] Edson M A, Nagaraja A K, Matzuk M M. The mammalian ovary from genesis to revelation. Endocrine Reviews, 2009, 30(6): 624–712

[47] Hsueh A J, Kawamura K, Cheng Y, Fauser B C. Intraovarian control of early folliculogenesis. Endocrine Reviews, 2015, 36(1): 1–24

[48] Emori C, Sugiura K. Role of oocyte-derived paracrine factors in follicular development. Animal Science Journal, 2014, 85(6): 627–633

[49] Lonergan P, Forde N, Spencer T. Role of progesterone in embryo development in cattle. Reproduction, Fertility, and Development, 2016, 28(2): 66–74

[50] Fair T, Lonergan P. The role of progesterone in oocyte acquisition of developmental competence. Reproduction in Domestic Animals, 2012, 47(S4): 142–147

[51] Lonergan P, Forde N.The role of progesterone in maternal recognition of pregnancy in domestic ruminants. Advances in Anatomy Embryology and Cell Biology, 2015, 216: 87–104

[52] Lonergan P. Influence of progesterone on oocyte quality and embryo development in cows. Theriogenology, 2011, 76(9): 1594–1601

[53] Diskin M G, Morris D G. Embryonic and early foetal losses in cattle and other ruminants. Reproduction in Domestic Animals, 2008, 43(S2): 260–267

[54] Krisher R L. In vivo and in vitro environmental effects on mammalian oocyte quality. Annual Review of Animal Biosciences, 2013, 1: 393–417

[55] Akagi S, Kaneyama K, Adachi N, Tsuneishi B, Matsukawa K, Watanabe S, Kubo M, Takahashi S. Bovine nuclear transfer using fresh cumulus cell nuclei and in vivo- or in vitro-matured cytoplasts. Cloning and Stem Cells, 2008, 10(1): 173–180

[56] Waddington C H. The epigenotype. Endeavour, 1942, 18–20

[57] Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science, 2010, 330(6004): 612–616

[58] Suzuki M M, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nature Reviews: Genetics, 2008, 9(6): 465–476

[59] Holliday R, Pugh J E. DNA modification mechanisms and gene activity during development. Science, 1975, 187(4173): 226–232

[60] Lee J T, Bartolomei M S. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell, 2013, 152(6): 1308–1323

[61] Wossidlo M, Nakamura T, Lepikhov K, Marques C J, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nature Communications, 2011, 2: 241

[62] Hou J, Liu L, Lei T, Cui X, An X, Chen Y. Genomic DNA methylation patterns in bovine preimplantation embryos derived from in vitro fertilization. Science in China Series C: Life Sciences, 2007, 50(1): 56–61

[63] Gu T P, Guo F, Yang H, Wu H P, Xu G F, Liu W, Xie Z G, Shi L, He X, Jin S G, Iqbal K, Shi Y G, Deng Z, Szabó P E, Pfeifer G P, Li J, Xu G L. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature, 2011, 477(7366): 606–610

[64] Tahiliani M, Koh K P, Shen Y, Pastor W A, Bandukwala H, Brudno Y, Agarwal S, Iyer L M, Liu D R, Aravind L, Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science, 2009, 324(5929): 930–935

[65] de Montera B, Fournier E, Shojaei Saadi H A, Gagne D, Laflamme I, Blondin P, Sirard M A, Robert C.Combined methylation mapping of 5mC and 5hmC during early embryonic stages in bovine. BMC Genomics, 2013, 14(1): 406

[66] Marcho C, Cui W, Mager J. Epigenetic dynamics during preimplantation development. Reproduction, 2015, 150(3): R109–R120

[67] Canovas S, Ross P J. Epigenetics in preimplantation mammalian development. Theriogenology, 2016, 86(1): 69–79

[68] Clark A T. DNA methylation remodeling in vitro and in vivo. Current Opinion in Genetics & Development, 2015, 34: 82–87

[69] Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nature Reviews: Genetics, 2017, 18(9): 517–534

[70] Bannister A J, Kouzarides T. Regulation of chromatin by histone modifications. Cell Research, 2011, 21(3): 381–395

[71] Tessarz P, Kouzarides T. Histone core modifications regulating nucleosome structure and dynamics. Nature Reviews: Molecular Cell Biology, 2014, 15(11): 703–708

[72] Wu H, Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell, 2014, 156(1–2): 45–68

[73] Cao Z, Li Y, Chen Z, Wang H, Zhang M, Zhou N, Wu R, Ling Y, Fang F, Li N, Zhang Y. Genome-wide dynamic profiling of histone methylation during nuclear transfer-mediated porcine somatic cell reprogramming. PLoS One, 2015, 10(12): e0144897

[74] Ross P J, Ragina N P, Rodriguez R M, Iager A E, Siripattarapravat K, Lopez-Corrales N, Cibelli J B. Polycomb gene expression and histone H3 lysine 27 trimethylation changes during bovine preimplantation development. Reproduction, 2008, 136(6): 777–785

[75] Canovas S, Cibelli J B, Ross P J. Jumonji domain-containing protein 3 regulates histone 3 lysine 27 methylation during bovine preimplantation development. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(7): 2400–2405

[76] Kishigami S, Mizutani E, Ohta H, Hikichi T, Thuan N V, Wakayama S, Bui H T, Wakayama T. Significant improvement of mouse cloning technique by treatment with trichostatin A after somatic nuclear transfer. Biochemical and Biophysical Research Communications, 2006, 340(1): 183–189

[77] Kohda T, Kishigami S, Kaneko-Ishino T, Wakayama T, Ishino F. Gene expression profile normalization in cloned mice by trichostatin A treatment. Cellular Reprogramming, 2012, 14(1): 45–55

[78] Ding X, Wang Y, Zhang D, Wang Y, Guo Z, Zhang Y. Increased pre-implantation development of cloned bovine embryos treated with 5-aza-2′-deoxycytidine and trichostatin A. Theriogenology, 2008, 70(4): 622–630

[79] Akagi S, Matsukawa K, Mizutani E, Fukunari K, Kaneda M, Watanabe S, Takahashi S. Treatment with a histone deacetylase inhibitor after nuclear transfer improves the preimplantation development of cloned bovine embryos. Journal of Reproduction and Development, 2011, 57(1): 120–126

[80] Liu W, Liu X, Wang C, Gao Y, Gao R, Kou X, Zhao Y, Li J, Wu Y, Xiu W, Wang S, Yin J, Liu W, Cai T, Wang H, Zhang Y, Gao S. Identification of key factors conquering developmental arrest of somatic cell cloned embryos by combining embryo biopsy and single-cell sequencing. Cell Discovery, 2016, 2: 16010

[81] Matoba S, Liu Y, Lu F, Iwabuchi K A, Shen L, Inoue A, Zhang Y. Embryonic development following somatic cell nuclear transfer impeded by persisting histone methylation. Cell, 2014, 159(4): 884–895

[82] Bernabucci U, Biffani S, Buggiotti L, Vitali A, Lacetera N, Nardone A. The effects of heat stress in Italian Holstein dairy cattle. Journal of Dairy Science, 2014, 97(1): 471–486

[83] Hansen P J. Exploitation of genetic and physiological determinants of embryonic resistance to elevated temperature to improve embryonic survival in dairy cattle during heat stress. Theriogenology, 2007, 68(S1): S242–S249

[84] Sakatani M. Effects of heat stress on bovine preimplantation embryos produced in vitro. Journal of Reproduction and Development, 2017, 63(4): 347–352

[85] Roth Z.Effect of heat stress on reproduction in dairy cows: insights into the cellular and molecular responses of the oocyte. Annual Review of Animal Biosciences,2017, 5: 151–170

[86] Roth Z. Physiology and endocrinology symposium: cellular and molecular mechanisms of heat stress related to bovine ovarian function. Journal of Animal Science, 2015, 93(5): 2034–2044

[87] Li G C, Werb Z. Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. Proceedings of the National Academy of Sciences of the United States of America—Biological Sciences, 1982, 79(10): 3218–3222

[88] Edwards J L, Hansen P J. Elevated temperature increases heat shock protein 70 synthesis in bovine two-cell embryos and compromises function of maturing oocytes. Biology of Reproduction, 1996, 55(2): 341–346

[89] Edwards J L, Ealy A D, Monterroso V H, Hansen P J. Ontogeny of temperature-regulated heat shock protein 70 synthesis in preimplantation bovine embryos. Molecular Reproduction and Development, 1997, 48(1): 25–33

[90] Hendrey J, Kola I. Thermolability of mouse oocytes is due to the lack of expression and/or inducibility of Hsp70. Molecular Reproduction and Development, 1991, 28(1): 1–8

[91] Hansen P J, Dobbs K B, Denicol A C. Programming of the preimplantation embryo by the embryokine colony stimulating factor 2. Animal Reproduction Science, 2014, 149(1-2): 59–66

[92] Avilés M, Gutiérrez-Adán A, Coy P. Oviductal secretions: will they be key factors for the future ARTs? Molecular Human Reproduction, 2010, 16(12): 896–906

[93] Seytanoglu A, Georgiou A S, Sostaric E, Watson P F, Holt W V, Fazeli A. Oviductal cell proteome alterations during the reproductive cycle in pigs. Journal of Proteome Research, 2008, 7(7): 2825–2833

[94] Tribulo P, Siqueira L G B, Oliveira L J, Scheffler T, Hansen P J. Identification of potential embryokines in the bovine reproductive tract. Journal of Dairy Science, 2018, 101(1): 690–704

[95] Tesfaye D, Lonergan P, Hoelker M, Rings F, Nganvongpanit K, Havlicek V, Besenfelder U, Jennen D, Tholen E, Schellander K. Suppression of connexin 43 and E-cadherin transcripts in in vitro derived bovine embryos following culture in vitro or in vivo in the homologous bovine oviduct. Molecular Reproduction and Development, 2007, 74(8): 978–988

[96] Gad A, Hoelker M, Besenfelder U, Havlicek V, Cinar U, Rings F, Held E, Dufort I, Sirard M A, Schellander K, Tesfaye D. Molecular mechanisms and pathways involved in bovine embryonic genome activation and their regulation by alternative in vivo and in vitro culture conditions. Biology of Reproduction, 2012, 87(4): 100

[97] Loureiro B, Bonilla L, Block J, Fear J M, Bonilla A Q, Hansen P J. Colony-stimulating factor 2 (CSF-2) improves development and posttransfer survival of bovine embryos produced in vitro. Endocrinology, 2009, 150(11): 5046–5054

[98] Dobbs K B, Khan F A, Sakatani M, Moss J I, Ozawa M, Ealy A D, Hansen P J. Regulation of pluripotency of inner cell mass and growth and differentiation of trophectoderm of the bovine embryo by colony stimulating factor 2. Biology of Reproduction, 2013, 89(6): 141

[99] Rizos D, Carter F, Besenfelder U, Havlicek V, Lonergan P. Contribution of the female reproductive tract to low fertility in postpartum lactating dairy cows. Journal of Dairy Science, 2010, 93(3): 1022–1029

[100] Maillo V, Rizos D, Besenfelder U, Havlicek V, Kelly A K, Garrett M, Lonergan P. Influence of lactation on metabolic characteristics and embryo development in postpartum Holstein dairy cows. Journal of Dairy Science, 2012, 95(7): 3865–3876

[101] Zhang B, Zheng H, Huang B, Li W, Xiang Y, Peng X, Ming J, Wu X, Zhang Y, Xu Q, Liu W, Kou X, Zhao Y, He W, Li C, Chen B, Li Y, Wang Q, Ma J, Yin Q, Kee K, Meng A, Gao S, Xu F, Na J, Xie W. Allelic reprogramming of the histone modification H3K4me3 in early mammalian development. Nature, 2016, 537(7621): 553–557

[102] Gao Y, Liu X, Tang B, Li C, Kou Z, Li L, Liu W, Wu Y, Kou X, Li J, Zhao Y, Yin J, Wang H, Chen S, Liao L, Gao S. Protein expression landscape of mouse embryos during pre-implantation development. Cell Reports, 2017, 21(13): 3957–3969

Acknowledgements

This work was funded by the National Natural Science Foundation of China (31672416), the Fundamental Research Funds for the Central Universities and the One Hundred Talents Program of Zhejiang University.

Compliance with ethics guidelines

Yanna Dang and Kun Zhang declare that they have no conflicts of interest or financial conflicts to disclose.

This article is a review and does not contain any studies with human or animal subjects performed by any of the authors.

RIGHTS & PERMISSIONS

The Author(s) 2018. Published by Higher Education Press. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0)