The Reprogramming Power of the Oocyte

Keith E Latham, Michigan State University, East Lansing, MI, United States
© 2018 Elsevier Inc. All rights reserved.

Introduction

Somatic cell nuclear transfer (SCNT) was first proposed as a way to assess genetic totipotency of somatic cells within the
context of whether genetic material was lost as cells differentiate. Little thought was initially given to the oocyte role in this
experiment. Subsequently, the remarkable power of oocytes to reprogram exogenous nuclei was dramatically demonstrated,
first in amphibians, and later in mammals, during the production of cloned animals. Cloning has been used for decades there-
after to generate cloned animals, first from embryonic cells, and subsequently from adult somatic cells, with valuable appli-
cation in basic research, agriculture production, transgenesis and biopharmaceutical production, endangered species
preservation, and most recently in the production of novel genetically modified animals capitalizing on advancement in
genome editing technologies.
Throughout all this rich history, the nature of ooplasmic factors that support genome reprogramming has remained elusive.
Many studies in the cloning field enumerate the many deficiencies and technical barriers to cloning, and report methods for
enhancing reprograming and cloning success by treating donor cells before nuclear transfer or by treating cloned constructs after
nuclear transfer. A more limited set of studies addresses ooplasmic factors in cloning, using a combination of genetic, proteomic,
and transcriptomic approaches, often coupled to in vitro reprogramming systems to better understand the functions of certain
molecules. These lines of study have increased our understanding of oocyte biology, the epigenetic mechanisms that help establish
each new life, and how the power of the oocyte might be more efficiently harnessed to achieve desired outcomes. Understanding the
nature of oocyte reprogramming capacity will require an appreciation for the unique biological processes that are driven by the
ooplasm during normal development, the changes in the cellular abundances and activities of the relevant factors during oocyte
maturation and embryo development, and the contributions of these ooplasmic changes to how the overall outcome is influenced
by the source of donor cell nuclei as a substrate for ooplasmic actions. Much of this insight has yet to emerge, making this an exciting
area of research.
In this article, the reprogramming power of the oocyte is considered both in terms of epigenetic changes that occur during
normal development and their contributions to normal events (Fig. 1), and in terms of changes imposed on somatic cell genome
following nuclear transfer, to what extent normal events are recapitulated or not recapitulated (Fig. 2), and the consequences for
cloned embryo viability. The article also considers reprogramming related to meiotic processes, and reprogramming related to
genome function. Both aspects of reprogramming are essential for viability.

Fig. 1 Summary of major epigenetic changes in mouse oocytes and fertilized embryos. Region in yellow highlight indicates the period during which
reprogramming events related to meiosis and initial transcriptional programming of the embryonic genome to support development occur. GVBD,
germinal vesicle breakdown.

212 Encyclopedia of Reproduction, 2nd edition, Volume 3 https://doi.org/10.1016/B978-0-12-801238-3.64456-2

 Oogenesis j The Reprogramming Power of the Oocyte 213

Fig. 2 Summary of major events associated with nuclear transfer in mice. Region in yellow highlight corresponds to the highlighted region in
Fig. 1. As indicated, recapitulation of the events during this period, related to both meiosis and gene transcription, is imperfect, with the result that
cloned embryos are markedly dissimilar to normal embryos (as indicated by s).

Oocyte and Donor Cell Genome Reprogramming Related to Meiosis

The critical cellular organ for meiosis is the meiotic spindle. Chromatin plays a crucial role in spindle formation. Without chromatin
spindles can form, but are highly disorganized. Chromatin in which histones H3 and H4 have undergone deacetylation allows
binding of RCC1, which in turn initiates the formation of a gradient of Ran-GTP emanating from the chromosome and locally
directing microtubule polymerization and chromosome attachment (Zierhut and Funabiki, 2015).
After SCNT, donor nuclei lose their nuclear envelopes, undergo chromatin condensation, and direct the formation of new spin-
dles within an hour (Gao et al., 2004). In principle, recapitulating spindle formation following SCNT provides a novel way of
studying oocyte meiosis. However, spindles that form after SCNT are defective. They fail to acquire many key proteins in the correct
abundances typical of well-formed spindles, and can have abnormal morphologies (Miyara et al., 2006; Han et al., 2010). Chro-
mosomes display gross deficiencies in congression and attachment to the spindle. These defects persist into the initial mitotic
cleavage divisions, and cloned embryos display increased incidences of aneuploidy.
Interestingly, spindles that form after transfer of embryonic nuclei (ECNT) are more normal (Miyara et al., 2006), indicating
some donor cell-dependent feature of chromatin affects the quality of the spindle that forms. A difference in overall histone
H3–H4 acetylation state could account for this. Histone deacetylase complexes are important for maintaining pluripotency and
developmental capacity, and for maintaining appropriate patterns of lineage-specific gene expression. These observations indicate
that the ability to deacetylate histones may be lost in the oocyte by the mature MII stage, that there may be insufficient opportunity
for deacetylation to occur before chromatin condensation, or both. Interestingly, the oocyte variant histone H1FOO assembles onto
chromatin within just 5 min of nuclear transfer (Gao et al., 2004), indicating the chromatin remodeling process initiates very
rapidly.
The relative timing of histone deacetylation and chromatin condensation may be disrupted with SCNT to mature MII stage
ooplasm, in which co-presence of factors that may normally appear and act in a specific temporal sequence during oogenesis
precludes the normal required sequence of events. Thus, while spindle formation after SCNT superficially appears to recapitulate
oocyte meiotic spindle formation, and while the mature oocyte contains all the factors needed to drive this seeming recapitulation,
the key ingredient of temporal specificity of action of some of these factors appears lacking.

Oocyte Reprogramming of Parental Genomes After Fertilization

Following SCNT, there is extensive transcriptional reprogramming of the donor nucleus, so that differentiated genomes cease to
express many somatic cell marker genes, and begin expressing pluripotency markers and other genes appropriate to early embryonic
stages. The transcriptional reprogramming power of the oocyte reflects the capacity to reprogram gamete genomes during each life
cycle. The sperm and egg genomes each directed the formation of highly specialized differentiated cell types. Accordingly, preparing
the embryonic genome for embryogenesis requires reprogramming gamete chromatin to an embryonic state. This process
214 Oogenesis j The Reprogramming Power of the Oocyte

encompasses many global changes in DNA methylation and histone acetylation (Fig. 1). The maternal and paternal genomes
undergo somewhat different transitions, particularly during the first two cell cycles after fertilization. For example, the paternal
genome, but not the maternal genome, undergoes active DNA demethylation during the 1-cell stage within 4 h of fertilization,
and then passive demethylation during cleavage. The paternal pronucleus lacks lysine 9 di- and tri-methylated histone H3, but
contains histone H3 mono-methylated at lysine 9 and lysine 27, and trimethyl-histone-K27 appears after DNA replication. The
maternal pronucleus contains lysine 9 di- and tri-methylated histone H3. With active demethylation of the paternal pronucleus
comes increased 5-hydroxymethylcytosine content generated by TET3, and inhibited by DPPA3 in the maternal pronucleus (Szabo
and Pfeifer, 2012). Reprogramming of the embryonic genome and onset of gene transcription are coupled to DNA replication.
Progression through the first S phase after fertilization establishes the ability to perform gene transcription, whereas progression
through the second S phase establishes the need for transcriptional enhancers (Latham, 1999). Ooplasmic changes accompany
these transitions. Early 1-cell stage cytoplasm is transcriptionally repressive and can exert an extended repressive effect on gene
expression after nuclear transfer (Latham, 1999). Such transitions may contribute to differences in cloning outcome observed by
varying the donor and recipient stages. Extensive changes in histone acetylation around the time of transcriptional activation,
also dependent on DNA replication, have been described (Latham, 1999). The oocyte-expressed SIN3A histone deacetylation
complex is required for transcriptional programming of the early embryo. Collectively, these observations demonstrate that the
oocyte is endowed with a wide range of factors that modify histone acetylation ad methylation and DNA methylation during early
cleavage divisions.

Ooplasmic Factors Participating in Exogenous Nuclear Reprogramming

Following nuclear transfer to MII stage oocytes, donor cell nuclear envelopes break down, chromosomes condense, a new spindle
forms, and chromosomes try to assemble onto the spindle. Despite the many defects observed, this sequence of events indicates that
many of the processes leading to the progression of oocytes to MII stage are recapitulated. As such, it is likely that hundreds of
proteins participate in these processes, and thus can be considered as participating in the overall reprogramming process. Thereafter,
gene expression must be reprogrammed to an embryonic state; the efficiency of that process affects cloned embryo characteristics
and viability (Fig. 2). Recent studies provide insight into some of the specific proteins that are likely involved.

Spindle Assembly Factors

The oocyte possesses the necessary factors required for chromatin condensation, and for subsequent spindle assembly. Spindle
assembly is linked mechanistically to chromosome condensation. During normal oogenesis, chromosomes undergo histone deace-
tylation and histone H1 becomes replaced with the oocyte specific variant H1FOO (De La Fuente, 2014). Histone deacetylation
allows binding of spindle assembly factors such as RCC1, RBBP4, and RBBP7, which allows the formation of a Ran-GTP gradient
emanating from the condensed chromosomes, to catalyze microtubule polymerization and spindle assembly (Zierhut and Funa-
biki, 2015). Interestingly, the Ran-GTP gradient is required for formation of the MII spindle, but may be dispensable for forming
the MI spindle (Zierhut and Funabiki, 2015). Thus, some of the factors that normally participate in progression to first meiotic
metaphase may be diminished in abundance from the MII stage oocyte when SCNT is performed, possibly accounting for the
many spindle defects observed after SCNT.

Cytoskeleton Components
In a recent genetic screen using recombinant inbred mice to identify genetic loci associated with the ability of SCNT embryos to
progress through cleavage, two cytoskeletal scaffold proteins emerged as the strongest genetic candidates for factors affecting early
clone development (Cheng et al., 2013). These factors may normally control the partitioning of transcription regulators between
nuclear and cytoplasmic compartments. This partitioning may be highly regulated to ensure the correct sequence of reprogramming
events in the early embryo. However, because the initial chromatin state of the donor genome is very different from gamete genomes
following pronucleus formation, the interactions of these cytoskeletal scaffold proteins with factors that modify chromatin may not
allow the normal sequence of reprogramming events to occur, leading to partial, or even chaotic, chromatin remodeling. Additional
nuclear roles for these proteins have not been examined.
Actin exists in the nucleus, where it may organize nuclear components, regulate chromatin architecture, bind and regulate avail-
ability of nuclear transcription factors to participate in transcription, and regulate RNA polymerase II complex function. A major
class of chromatin modifying proteins, the SMARC (SWI/SNF-related matrix-associated, actin-dependent regulator of chromatin)
family of chromatin regulators, interacts with actin. Studies in Xenopus oocytes revealed that the Wave1 protein, which participates
in actin filament organization, is involved in reprogramming (Miyamoto et al., 2013). Wave1 binds to transcription factors in the
nucleus and regulates RNA pol II-dependent transcription. Nuclear actin polymerization regulates expression of the pluripotency
factor Oct4/Pouf5f1.
Intermediate filaments may also contribute to reprogramming. Vimentin is detected in oocytes and associates with condensing
chromatin after SCNT; inhibiting its function negatively affects development of cloned embryos, but not parthenogenetic or fertil-
ized control embryos (Kong et al., 2014).
 Oogenesis j The Reprogramming Power of the Oocyte 215

Chromatin, Epigenetic, and Transcriptional Regulators

Oocytes are endowed with a rich supply of specialized histone variants, as well as factors that modify histones. Together, these
proteins play significant roles in reprogramming genomes. Oocytes contain a unique form of linker histone H1, denoted
H1FOO, which binds chromatin more tightly than somatic H1, and rapidly assembles onto chromatin after SCNT (Gao et al.,
2004). Oocyte-expressed histone H3.3 is required for reprogramming, and cannot be substituted by donor cell expressed H3.3
(Wen et al., 2014). Two variants of histone H2, previously denoted as testis specific (TH2A and TH2B) are also expressed in oocytes,
and can enhance induced pluripotency in fibroblasts (Huynh et al., 2016). Another oocyte factor, arginine methyltransferase 7
(PRMT7), which methylates H2A, H4, and other chromatin proteins (Miranda et al., 2004), also enhances induced pluripotency
(Wang et al., 2016). Histone demethylases are also expressed maternally (Page-Lariviere and Sirard, 2014). Oocytes also contain
multiple histone deacetylases, including HDC1, HDAC2, HDAC3, and other chromatin modifying complexes that interact with
HDACs activities, such as SIN3A and nucleoplasmin 2, as well as histone chaperone ASF1, which participate in reprogramming.
Additional chromatin regulators are involved in DNA cytosine demethylation, such as DNA methylcytosine dioxygenase TET3,
an activity that is inhibited in the maternal genome by the oocyte expressed developmental pluripotency associated protein
DPPA3/PGC7/STELLA (Szabo and Pfeifer, 2012), contributing to active demethylation preferentially in the paternal pronucleus.
Cullin-ring finger ligase-4, its linker protein DBB1, and substrate adaptor VPRBP/DCAF1 activate TET methylcytosine dioxygenases.
Other transcription factors that contribute to oocyte reprogramming function include the transcriptional repressor RE1 silencing
transcription factor (REST) (Kong et al., 2016), and oocyte-expressed Gli-like transcription factor GLIS1, which is required for
cleavage development and enhances induced pluripotency (Maekawa et al., 2011).
While the oocyte possesses this diverse range of activities, reprogramming with SCNT is limited, and treating either donor cells or
SCNT constructs with epigenetic drugs has proven beneficial. These include HDAC inhibitors such as trichostatin A, Scriptaid, val-
proic acid, oxamflatin, and others. However, excessive treatment with these epigenetic drugs can be detrimental, possibly due to
non-specific gene deregulation, loss of imprinting, or loss of other key functional chromatin features. Increased histone acetylation
may re-activate some genes contributing to early embryogenesis, but may also inhibit correct chromatin condensation and segre-
gation, as discussed above. Donor cells can also be treated with protamines to enhance cloning (Czernik et al., 2016).

Telomerase and Resetting Replicative Potential

Production of cloned animals, and especially serial cloning through multiple generations or production of clones from aged animals
or senescent cells, indicate that the ooplasm has the ability to reset replicative potential, and elongation of telomeres in cloned animals
has been reported. This capacity interacts with donor cell characteristics, as both cell type and species affect telomere lengthening.

Mitochondrial and Metabolic Factors

A key component of oocytes is the mitochondrial population, which normally are exclusively matrilineally transmitted. SCNT can
create mitochondrial heteroplasmy, although this appears somewhat variable, and subject to complex interactions that differ, as
seen by variations in outcomes with different inter-species SCNT donor-recipient combinations. Nuclear reprogramming is an
ATP-dependent, energy-intensive process. Metabolic disturbances have been reported in SCNT embryos, and it has been suggested
that this negatively affects protein synthesis. The metabolic disturbances may reflect a combination of stress-induced responses and
delayed reprogramming affecting embryonic physiology. Mitochondria in the oocyte and early embryo are electron dense with few
transverse cristae indicative of reduced ATP-production potential, and become less dense, elongate, and develop transverse cristae
during preimplantation development. The initial mitochondrial state may limit ATP production and limit reprogramming capacity.
Compatibility between donor nucleus and oocyte mitochondria, and ability of the ooplasm to direct correct transcriptional regu-
lation of mitochondrial genes are likely key factors in defining oocyte reprogramming potential.

Immediate Versus Later Reprogramming Events

Studies of SCNT mouse embryos revealed persistence of somatic cell-like features well into cleavage. Cloned embryos display a pref-
erence for somatic cell culture medium over embryo culture medium formulations, a preference for glucose containing media, and
a preference for atmospheric oxygen concentration during culture (Latham, 2005). Additionally, cDNA microarray studies revealed
hundreds of mis-regulated genes at the two-cell stage, including aberrant expression of transcription factors, which may direct aber-
rant transcription in a hierarchical manner, accounting for the large number of aberrantly regulated genes (Vassena et al., 2007). At
later stages, cloned embryos display aberrant regulation of protein localization, and aberrant gene expression continues (Latham,
2014). Some transcription factors remain associated with the donor genomes after SCNT, and somatic cell-expressed genes continue
to be expressed. These observations indicate that reprogramming is slow and likely continues throughout cleavage stages. This likely
creates difficulties for providing cloned embryos with optimized culture environments, as their cellular and molecular characteris-
tics would continue to evolve during cleavage development. Treatment of donor cells with epigenetic drugs or chromatin modifying
proteins may provide a head start on reprogramming, which could improve outcome.
One study found that inhibiting DNA replication after nuclear transfer inhibited reprogramming and activation of pluripotency
markers (Wang et al., 2014). This suggests that, just as DNA replication is required for embryonic genome reprogramming, so too it
216 Oogenesis j The Reprogramming Power of the Oocyte

contributes to reprogramming during cloning. This is also consistent with persistence of somatic cell characteristics during cleavage,
indicating that reprogramming is a slow process that is facilitated by passage through embryonic cell cycles and associated rounds of
DNA replication.
Species differences may exist in the pace of reprogramming. One study reported more rapid reprogramming with nuclear transfer
to mitotically arrested zygotes in mouse as compared to human (Egli et al., 2011). This difference may reflect different kinetics of
regulating ooplasm components following fertilization.

Relationship Between Oocyte Reprogramming Factors and Reprogramming Factors Used to Induce Pluripotency

The study of oocyte reprogramming factors has expanded in recent years through new initiatives to discover factors that can enhance
induced pluripotency in cultured somatic cells. For example, oocyte-expressed histone variants, nucleoplasmin, and GLIS1,
activation-induced cytidine deaminase, and geminin can enhance cellular reprogramming to make induced pluripotent stem cells
(iPSCs) (Huynh et al., 2016; Maekawa et al., 2011). Oocyte expressed PRMT7 can substitute for SOX2 in the iPS protocol (Wang
et al., 2016). Transcriptome comparisons between oocytes of different species have led to “candidate oocyte reprogramming factors”
that are being tested for use in cellular reprograming. Oocyte germinal vesicle extracts and oocyte extracts from different species have
been considered in cellular reprogramming (Tokmakov et al., 2016). Genes elevated in expression in iPSCs relative to embryonic
stem cells have been compared to oocyte transcriptomes for further selection of candidates. Reciprocally, factors used in making iPSCs
have been used to facilitate reprogramming with SCNT. The discovery of different combinations of chromatin modifiers and other
factors that can be used in combination to convert somatic cells in culture to pluripotency indicates that many pathways to plurip-
otency may exist, and that extreme overexpression of exogenous factors can overwhelm prior programming by transforming chro-
matin states at pluripotency-related loci. Discovering which of these pathways also operate during gametogenesis, which do not,
and what are the common downstream mechanisms leading to pluripotency should reveal much new knowledge about how game-
togenesis generates genomes that can direct the formation of a new individual. In addition, discovering how the oocyte components
(cytoplasmic mRNAs, proteins) interact with the two gamete genomes to unlock the gametic programming should prove fascinating.

Conclusions

The oocyte is truly a remarkable cell, being endowed with the ability to vastly restructure chromatin, both in preparation for meiosis,
and to generate one of two gamete genomes that must unite to form a new life. The oocyte also contains factors that interact with the
sperm-derived genome to ready it for function, as well as factors that maintain and modify epigenetic information related to
genomic imprinting, and factors that prepare the embryonic genome for transcription and enable transcription to be properly regu-
lated. No other cell type possesses this capacity. The identification of factors that contribute to reprogramming during cloning by
nuclear transfer, combined with identification of factors that enable induced pluripotency in vitro have shed important new light on
the nature of ooplasm reprogramming factors. But the factors so far identified are comparatively few in number, and most are well-
known for chromatin remodeling and transcriptional control in other contexts. Along with the identification of these factors has
come the realization that the oocyte must contain many such factors, and that numerous factors must work in combination to
accomplish the overall goal of reprogramming the oocyte genome for meiosis, and reprogramming pronuclei and the embryonic
genome during early cleavage to support embryogenesis. Many of the reprogramming factors in the oocyte likely work in comple-
mentary pairs, which modify the oocyte and pronuclear genomes, and then reverse those modifications at the appropriate stages.
This suggests that the activities of these factors must be coordinated with and regulated by signaling pathways within the oocyte that
respond to exogenous stimuli as well as endogenous cues. This further implies that the oocyte will be sensitive to external insults,
but that redundancies in functions and partitioning of functions between multiple factors may provide resistance to sustain overall
oocyte quality even in the face of adverse environmental conditions. A better understanding of those functional redundancies and
partitioning could provide new approaches to enhance oocyte quality for a range of purposes, as well as methods to enhance success
of cloning and creation of induced pluripotent stem cells in vitro.
Using oocyte factors to enhance induction of pluripotency, using iPS factor to enhance cloning outcome, or treating donor cells
or clone constructs with epigenetic drugs all show some success and some promise. But all these approaches carry risk of incorrect
reprogramming, with unintended effects on some target genes potentially negating favorable effects at other genes, as well as risk of
disrupting essential imprinting information and other epigenetic information that guides early development and even determines
adult phenotype. Additional attention to reprogramming chromatin to a state that can work with oocyte factors to enhance chro-
mosome congression and spindle quality could also be helpful.

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