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Genome activation and architecture in the early
mammalian embryo
Natasha Jansz1 and Maria-Elena Torres-Padilla1,2
Over the last decade, our understanding of how the genome is
packaged in three dimension within the nucleus has grown
considerably. This is largely due to advances in high-throughput
genomics assays to study higher order chromatin organization.
Our knowledge of the structures adopted by the chromatin has far
preceded our understanding of function and mechanism. An
outstanding question has been how are such structures
established. Recently, a suite of genomics assays has been
adapted for low-input material, making it possible to apply them to
the pre-implantation mammalian embryo. For the first time,
chromatin topology and associations with the nuclear lamina have
been described in the earliest stages of murine development.
These studies have revealed the dynamics with which higher-order
chromatin architecture is established in vivo. Additionally, they
have yielded some intriguing findings that will pave the way for
futures studies into the mechanisms underlying the establishment
of three dimensional genome organization. Here, we discuss
findings on how embryonic chromatin is dynamically organized
within the nucleus throughout preimplantation development, and
the outline a number of outstanding questions that will be exciting
to address in the future.
Addresses
1 commences. In mouse, the embryonic genome is tran-
Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München,
D-81377 München, Germany
2
Faculty of Biology, Ludwig-Maximilians Universität, München,
Germany
Corresponding author: Torres-Padilla, Maria-Elena
(torres-padilla@helmholtz-muenchen.de)
Current Opinion in Genetics & Development 2019, 55:52–58
This review comes from a themed issue on Genome architecture and
expression
Edited by Ana Pombo and Wendy Bickmore
https://doi.org/10.1016/j.gde.2019.04.011
0959-437X/ã 2018 Elsevier Inc. All rights reserved.
Introduction
Early embryogenesis represents a dramatic example of
chromatin remodeling in mammalian cells. Reprogram-
ming of the parental genomes enables two terminally
differentiated cells, the sperm and the oocyte, to give rise
to a totipotent embryo. The mature gametes are largely
Current Opinion in Genetics & Development 2019, 55:52–58
transcriptionally inert. The oocyte, arrested in metaphase
II, possesses highly condensed and segregated meiotic
chromatin. The genome of mature sperm is also hyper-
condensed through the incorporation of protamines in
place of histones. Following fertilization, a pool of mater-
nally loaded mRNA and proteins enable zygotic genome
activation (ZGA) and the consequent maternal-to-zygotic
transition.
Upon fertilization, the oocyte resumes the second meiotic
division, and protamines in the paternal genome are
rapidly exchanged for maternally supplied histones.
The two genomes decondense and remain segregated
as pronuclei. Histone modifications are deposited de novo
on the paternal chromatin, while histone modifications
associated with constitutive heterochromatin are remo-
deled from the maternal chromatin. Asymmetries
between the maternal and paternal chromatin are main-
tained throughout preimplantation development and are
gradually resolved by the blastocyst stage [1,2,3]. As
development ensues maternal products are progressively
degraded and transcription from the zygotic genome
scribed from the zygote stage, although the major wave of
ZGA occurs in the 2-cell embryo [reviewed in Ref. [4]].
Our knowledge on the chromatin landscape throughout
pre-implantation development has been propelled by a
sudden increase in low-input genomics assays applied
predominantly to the mouse embryo. This review is
focused on genome activation and architecture during
murine preimplantation development, drawing on find-
ings in other vertebrate species where relevant.
That the genome adopts a non-random position within the
nucleus and with respect to the nuclear periphery is now
well established. However, the extent to which this posi-
tion is causally related to genome function is still a matter of
investigation. Genome positioning within the embryonic
nucleus is atypical and changes extensively throughout
preimplantation development [5,6]. Whereas in somatic
cells, the major satellite repeats that comprise pericentro-
meric heterochromatin form DAPI-dense chromocentres,
in the oocyte, zygote, and 2-cell stage embryo pericentro-
meric chromatin is arranged radially surrounding nucleolar-
like bodies (NLBs) [7]. A similar distribution of
pericentromeric chromatin is observed upon somatic cell
nuclear transfer, suggesting that the specific chromatin
architecture adopted by the zygote is important for repro-
gramming [8]. Positioning of pericentromeric chromatin at
the NLB is necessary to initiate repressive heterochromatin
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 Genome architecture in mammalian preimplantation development Jansz and Torres-Padilla 53

[9]. Indeed, perturbing the NLB localization of pericen-
tromeric chromatin results in defective silencing of major
satellites and arrested development. These findings pro-
vided the first evidence that three dimensional nuclear
organization has a functional role in genome regulation of
the early embryo. While the mechanism underlying NLB
directed heterochromatin formation is unclear, peripheral
heterochromatin has been observed to stochastically asso-
ciate with nucleoli in somatic cells, raising the possibility of
a functional relationship between peripheral heterochro-
matin and nucleoli associated chromatin [10,11].
High-throughput chromatin conformation capture-based
(Hi-C) assays, applied to a host of somatic cells have
revealed hierarchical principles of genome organization
(Figure 1) [12,13]. DNA can form loops, bringing distal
regulatory elements into proximity with target genes.
Looping events tend to be constrained within topologi-
cally associated domains (TADS) that range from 40 kb to
3 Mb in size. Genes within a TAD are associated with a
similar chromatin signature, transcriptional outcome, and
replication timing. The prevailing model to explain loops
and TADs is loop-extrusion [14,15]. Multiple TADs
associate to form A and B compartments, which are
largely enriched for euchromatin and heterochromatin,
respectively. Intra-chromosomal contacts are highly
favoured over inter-chromosomal interactions. This is
in agreement with observations from chromosome paint-
ing experiments, which find chromosomes occupying
discrete territories within the nucleus [16].
Low-input genomics approaches have revealed the distribu-
tion of specific chromatin modifications in the mouse embryo
[17–19]. Advances in low-input genomic assays have now
allowed mapping of genomic regions associated with the
nuclear lamina, and chromatin topology throughout murine
preimplantation development [3,20,21,22,45]. Com-
plemented by genome accessibility profiles [23], these
studies have extended our knowledge beyond microscopic
observations to describe three dimensional genome architec-
ture throughout preimplantation development in much
greater detail. These analyses have provided unexpected
findings, which will pave the way for new conceptual avenues
to address the mechanisms underlying the establishment of
nuclear organization.
Mapping nuclear positioning and genome
topology in the preimplantation embryo
Genome positioning proximal to the nuclear lamina is
globally associated with transcriptional repression [24].

Figure 1

Looping Topologically A & B Compartments Nuclear Positioning

Associated Domains (Chromosome Territories)

Current Opinion in Genetics & Development

Principles of genome organization.

From left to right: chromatin can loop by forming long-range interactions between DNA sequences (black) that are not close in linear sequence,
but are brought together in 3D space, mediated by structural proteins. They include but are not limited to, Cohesin mediated loops (green) and
Polycomb mediated loops (sky blue). Topologically associated domains (TADs) comprise regions of the genome that interact with each other more
frequently than with adjacent regions of the genome, forming a self-interacting domain (depicted in navy blue and forest green). In mouse, TAD
boundaries are demarcated by the insulator protein CTCF (red) and the Cohesin complex (green). TADs with similar epigenetic profiles form
stronger inter-domain interactions and are organized into compartments (blue and orange). A compartments are associated with active
transcription, whereas B compartments are associated with transcriptional repression. Each chromosome occupies a distinct territory within the
nucleus (individual chromosome are represented by different colors) and forms very few trans-chromosomal interactions. Hi-C contact map
representations of each structure are depicted below. Image of chromosome territories adopted from Ref. [44].

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54 Genome architecture and expression

Lamina associated domains (LADs) characterized in
somatic cells are in the range of megabases, and tend
to be gene-poor, AT-rich, late-replicating, heterochro-
matic sequences contained within B compartments
[12,25]. Accordingly, early electron microscopy experi-
ments revealed that DNA in somatic cells is visibly
concentrated at the nuclear periphery [26]. Given the
distinct composition and organization of heterochromatin
during early embryogenesis, it was unclear whether these
principles would hold true in the preimplantation
embryo. Indeed, chromatin does not appear to be con-
centrated at the nuclear periphery in the early zygotic
pronuclei, and is only poorly visible in the early 2-cell
embryo [27]. Furthermore, chromosome painting in
bovine preimplantation embryos suggests that gene-poor
chromosomes do not associate with the nuclear periphery
until ZGA [28]. Atypical heterochromatin organization in
relation to the nuclear periphery has been previously
observed in photoreceptor cells and upon cellular senes-
cence [29–31]. These observations indicate that the chro-
matin is also atypically organized within the nucleus
during preimplantation development.
A recent study used single-cell and low-input DNA
adenine methyltransferase identification (DamID) to
map LADs in the mature interphase oocyte and preim-
plantation embryo [45]. LADs are present from as early as
the zygote stage, indicating that LAD formation may be
an initial hallmark of nuclear organization. Zygotic LADs
correspond to LADs identified across multiple somatic
cell types, they are similarly AT-rich relative to inter-
LADs and anti-correlate with DNA hypersensitive
regions. Chromatin shifts from the nuclear periphery
between the zygote and the 2-cell stage. The 2-cell stage
LADs are still AT-rich; however, the difference between
the LADs and inter-LADs is not as marked, and a
significant number of 2-cell stage LADs belong to the
A-compartment (Figure 2). The dynamic movement of
LADs likely reflects chromatin reprogramming that
occurs concomitant with ZGA, as LAD repositioning
largely correlates with transcriptional changes; regions
that are internalized show a global increase in expression,
whereas those that move to the periphery tend to be
silenced. Thus, it would seem that the embryo is not an
exception, and LADs are clearly structured from as early
as the zygote stage.
Remarkably, LADs are undetectable in the mature inter-
phase oocyte, further highlighting distinct chromatin orga-
nization in the oocyte. This indicates that LAD organiza-
tion is not inherited through the maternal germline, but is
instead established de novo after fertilization. It will be
important to determine whether memory of nuclear lamina
associations is carried through the paternal germline. Since
LaminB1 is not expressed in the sperm, different experi-
mental strategies will have to be utilized [32].

Figure 2

TADs
Compartments

SN Oocyte Gametes Zygote 2-Cell 8-Cell Blastocyst

Maternally Inherited Totipotency Pluripotency

Transcripts Zygotic Genome Activation
Current Opinion in Genetics & Development

Chromatin organization dynamics throughout murine preimplantation development.

TAD and compartment dynamics are depicted in red, and red and blue, respectively, for the paternal (top) and maternal (bottom) genomes.
Embryonic nuclei are depicted in pale blue, DNA in blue, and somatic LADs in orange. In the 8-cell embryo and blastocyst a single blastomere
has been enlarged to depict LADs. In the mature oocyte, DNA concentrates around the nucleolar like body, and LADS, TADs and compartments
are not detectable. The sperm on the other hand largely recapitulates somatic principles of chromatin organization, displaying an increase in very
long-range and trans-chromosomal interactions. Upon fertilization the de novo formation of weak loops occurs in the maternal genome. LADs can
be observed in both genomes. At the 2-cell stage, there is a reorganization of LADs, largely mimicking patterns in expression. Long-range
chromatin interactions consolidated throughout development, and the chromatin architecture and LADs in the inner cell mass of the blastocyst
resemble those identified in somatic cells.

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 Genome architecture in mammalian preimplantation development Jansz and Torres-Padilla 55

In contrast to somatic cells [33], chemical inhibition of
DNA replication does not perturb embryonic LAD for-
mation. This anticipates different mechanisms for LAD
establishment and LAD maintenance. Notwithstanding,
that zygotic LADs resemble somatic LADs raises the
possibility that nuclear association is an intrinsic property
of the underlying genetic sequence. Because of an anti-
correlation between paternal LADs and H3K4me3, a
modification typically associated with active promoters,
authors overexpressed the demethylase Kdm5b. Kdm5b
overexpression ablated paternal, but not maternal LADs.
Together these data raise the possibility that intrinsic
sequence specificity drives initial LAD formation that is
consolidated and maintained by a target of Kdmb5, and
potentially through alternative pathways in the maternal
genome (Figure 3). These findings also predict that in
addition to different chromatin compositions and histo-
ries of the paternal genomes, there are different mecha-
nisms underlying their nuclear organization in the earliest
stages of preimplantation development.
In contrast to the rapid establishment of LADs in the
zygote, the hierarchical, three-dimensional organization
of the genome appears to be established and strength-
ened throughout preimplantation development (Fig-
ure 2). Four studies have described long-range chromatin
interactions in germ cells and throughout murine preim-
plantation development using either low input or single
nucleus Hi-C protocols [3,20,21,22]. Oocyte matu-
ration is associated with a marked loss in structure and an
increase in interactions greater than 400 kb [20]. This
likely reflects transcriptional repression and chromatin

Figure 3

(a) (c) Wild Type

Kd

Boundary
m5
b

Element

Cohesin Architectural
Protein

(b) Scc1Δ/Δ

Inhibition of
Replication
Aphidicolin Reduced Cohesin Residency
48 hours
WaplΔ/Δ

2-Cell Untreated

Inhibition of
Transcription

α-Amanatin
24 hours Increased Cohesin Residency
Current Opinion in Genetics & Development

Mechanistic insights into chromatin organization in the preimplantation embryo.

(a) LADs (orange) in the paternal genome are ablated upon Kdm5b (red) overexpression in the zygote, suggesting that a target of Kdm5b’s
demethylase activity has a role in maintaining LADs potentially by excluding non-LAD regions from the periphery. (b) The consolidation of TAD
depends on DNA replication, but not on zygotic genome activation. (c) Cohesin (green) mediated looping is implicated in the establishment on
higher order chromatin structure in the zygote. Reducing chromatin associated Cohesin by Scc1 knockout results in a loss of zygotic looping
events. Conversely, increasing Cohesin residency on the chromatin by knocking out Wapl results in an increase in zygotic loops. Cohesin
mediated looping in the zygote is regulated by yet unidentified boundary elements and architectural proteins.

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56 Genome architecture and expression
condenzation around the NLB. The meiotic chromatin of
the metaphase II (MII) stage oocyte also lacks detectable
TADs and compartments, resembling mitotic chromatin
of somatic cells. In sperm however, loops, TADs, and
compartments can be detected [20,22]. When com-
pared with somatic cells there are increased long-range
interactions greater than 2 Mb, and more frequent trans-
chromosomal interactions detected in sperm. This likely
reflects the highly condensed chromatin packaged into a
small nuclear volume by protamines. Upon fertilization,
the maternal and paternal chromatin are rearranged in the
zygote. However, there are some slight discrepancies
among the three groups’ interpretations of the three-
dimensional organization of the zygotic genome.
Despite different interpretations, all studies confer that
zygotic TAD and loop structure is weaker. Contact maps
generated from low input Hi-C data from the zygote show
very little structure. The typical diagonal and plaid
structures, indicative of TADs and compartments respec-
tively, are absent on heatmaps [3,22]. An aggregate
analysis calculating insulation scores at TAD boundaries
determined in the inner cell mass of the blastocyst, found
insulation in the zygote to be modest, progressively
strengthening over development (Figure 2). Indeed,
DNA FISH reveals TAD violations within individual
nuclei occur more frequently in the zygote [20,22].
Toward understanding function and
mechanism of embryonic genome
architecture
Targeted approaches have provided mechanistic insight
into how genome organization is established. Inhibiting
DNA replication by Aphidicolin treatment for two days
prevented the consolidation of TADs and arrested devel-
opment (Figure 3) [22]. The mechanisms by which
replication could impact topological genome organiza-
tion remain to be investigated. One possibility could be
through cell cycle-dependent binding of loop extrusion
factors [34]. The role of global transcription on three-
dimensional genome organization has been addressed by
performing low-input Hi-C on 2-cell embryos treated
with a-Amanitin, which prevents ZGA [16]. It has long
been known that development arrests under these con-
ditions [35], yet developmental TAD consolidation still
proceeds (Figure 3). This finding was somewhat surpris-
ing, as it has been speculated that RNA polymerase II
could function as an insulting element due to its enrich-
ment at TAD boundaries, and that chromatin segregation
in lower organisms can be explained by transcription
[12,36]. TAD formation in Zebrafish also proceeds nor-
mally in absence of transcription [37]. These data would
suggest that the three-dimensional organization of ver-
tebrate genomes is not fully dependent on transcription,
and the correlation between RNA PolII, transcription
and boundary elements may arise as a result of three-
dimensional genome organization.
Current Opinion in Genetics & Development 2019, 55:52–58
Zygotes lacking Cohesin function through the maternal
and zygotic deletion of Scc1, cannot form loops or TADs but
notably display an increase in compartment strength [21].
Conversely, increasing the residency of Cohesin bound to
the chromatin by knocking-out Wapl results in enhanced
TAD and loop strength, but weaker compartments (Fig-
ure 3). These experiments highlight an important role for
Cohesin-mediated loops in TAD consolidation of the pre-
implantation mouse embryo, and agree with observations
that support different and opposing mechanisms for TAD
and compartment formation [38].
Studies of genome topology and nuclear organization
have revealed the global dynamics with which genome
structure is established in the earliest stages of mamma-
lian development. Because of the paucity of material, the
resolution achieved does not allow for the identification of
novel genetic or chromatin associated features that may
govern genome architecture in the early embryo. Analysis
of accessible regions distal to the transcription start site of
genes expressed in the 2-cell embryo revealed a remark-
able enrichment of transposable elements marked by
H3K27ac, a histone modification typically associated with
active enhancers [23]. Transposable elements can func-
tion as alternative promoters to drive the expression of a
subset of genes during ZGA [39]. These data suggest that
repetitive elements may additionally function globally as
enhancer elements over long distances during pre-
implantation development. Transposable elements are
similarly accessible in the human preimplantation
embryo [40], raising the possibility that coopting trans-
posable elements as enhancers is a conserved feature of
mammalian development.
Motif analysis of accessible distal regulatory elements
found CTCF motifs highly enriched only in the inner cell
mass of the blastocyst, three days after fertilization [23].
This observation offers a possible explanation for obscure
TAD structures observed in the early embryo; the loop
extrusion model proposes that DNA is processed through
a Cohesin ring, and upon encountering CTCF bound to
divergent motifs, processing stops [14]. Thus, while
Cohesin mediated looping is important for genome struc-
ture in the early embryo, limited CTCF binding may
result in increased Cohesin processivity, therefore,
reduced insulation at TAD boundaries. It is possible that
other factors may interact with the Cohesin complex to
regulate chromatin topology before blastocyst formation.
Indeed, work in Drosophila has highlighted the role of the
pioneer transcription factor Zelda in boundary formation
at the onset of ZGA [41]. Given transcription factors can
regulate chromatin topology in somatic cells [42–44], it
will be important to study the role of specific transcription
factors in dictating chromatin organization in preimplan-
tation development. Intriguingly, in humans CTCF
motifs become accessible around the time of major
ZGA at the 8-cell stage [40]. It will, therefore, be
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 Genome architecture in mammalian preimplantation development Jansz and Torres-Padilla 57
Box 1 Outstanding questions
Are the changes in described structures a cause or consequence of
ZGA and development?
What is the function of peripheral nuclear positioning?
What is the interplay between positioning at the nuclear lamina, and
at other features such as the NLB, which has a known silencing role?
What is the molecular mechanism by which Kdm5b is involved in
LAD formation?
What effect does altering higher order chromatin organization have
on ZGA and development?
In addition to the Cohesin complex, what factors drive the estab-
lishment of higher order chromatin architecture in the early embryo?
What mediates or limits the binding of architectural proteins in the
preimplantation embryo?
Beyond correlation: cause and consequence, functional
relationships
interesting to see whether TADs and loops are consoli-
dated earlier in human preimplantation development,
coincident with ZGA.
Conclusion
Advances in low input genomics assays have allowed for the
first high-resolution, genomic descriptions of chromatin
architecture in the preimplantation mammalian embryo.
They have revealed the dynamics with which higher order
chromatin architecture is established in mouse, and that
many principles of genome organization identified in
somatic cells hold true in the early embryo. These studies
have created the framework on which to base important
studies into the function and mechanisms underlying the de
novo establishment of genome architecture (see Box 1). To
address these questions, manipulation of the embryo to
perturb candidate factors involved in genome architecture
is required. Such hypotheses-driven work will aid in the
identification of novel factors involved in preimplantation
development and inform models that can explain the
establishment of hierarchical genome organization. This
work will also enable fundamental questions in genome
biology pertaining to the role three dimensional organiza-
tion in regulating gene expression and development to be
addressed in the coming years.
Conflict of interest statement
Nothing declared.
Acknowledgements
We thank A. Burton for critical reading of the manuscript. Work in the
Torres-Padilla lab is funded by the Helmholtz Association, the German
Research Council (CRC 1064) and H2020 Marie-Curie Actions ITN
EpiSystem and ChromDesign.
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