Versatile roles for histones in early development
Yuki Shindo, Madeleine G. Brown and Amanda A. Amodeo
Abstract
The nuclear environment changes dramatically over the
course of early development. Histones are core chromatin
components that play critical roles in regulating gene expression
and nuclear architecture. Additionally, the embryos of
many species, including Drosophila, Zebrafish, and Xenopus
use the availability of maternally deposited histones to time
critical early embryonic events including cell cycle slowing and
zygotic genome activation. Here, we review recent insights into
how histones control early development. We first discuss the
regulation of chromatin functions through interaction of histones
and transcription factors, incorporation of variant histones,
and histone post-translational modifications. We also
highlight emerging roles for histones as developmental regulators
independent of chromatin association.
Addresses
Department of Biological Sciences, Dartmouth College, Hanover, NH
03755, USA
Corresponding authors: Amodeo, Amanda A (amanda.amodeo@dartmouth.edu);
Shindo, Yuki (yuki.shindo@dartmouth.edu)
Current Opinion in Cell Biology 2022, 75:102069
This review comes from a themed issue on Cell Nucleus
Edited by Kazuhiro Maeshima and Eran Meshorer
For a complete overview see the Issue and the Editorial
Available online xxx
https://doi.org/10.1016/j.ceb.2022.02.003
0955-0674/© 2022 Elsevier Ltd. All rights reserved.
Introduction
Histones are the core components of eukaryotic chromatin.
Two pairs of each of the four nucleosomal histones
(H2A, H2B, H3, and H4) form an octamer that
wraps w146 base pairs of DNA to form a nucleosome
while the linker histone H1 controls nucleosome
spacing and larger chromatin conformation [1e3]. Histone
occupancy, positioning, exchange, and posttranslational
modifications (PTMs) regulate transcription
initiation and elongation, and incorporation of
specific histone variants or PTMs can mark genomic
features such as sites of DNA damage or heterochromatin
[4e6].
The chromatin landscape changes dramatically during
development. In sexually reproducing species, the sperm
pronucleus must first be decondensed and then fused
with the maternal pronucleus during the process of
fertilization. In most species, the initial chromatin state
is “naive”; transcription is largely inactive, there is a
relative absence of histone PTMs, and the threedimensional
organization of the genome is not well
established. As development progresses, cells within the
embryo acquire cell type-specific transcriptional profiles,
PTMs, and chromatin architecture [7,8]. Prior to zygotic
genome activation (ZGA), development is driven by
maternally deposited components. ZGA coincides with
cell cycle remodeling in many species and this coordinated
transition is referred to as the mid-blastula transition
(MBT) [9e11] (Figure 1). How the MBT is
temporally regulated has been a fascinating and important
question in developmental biology.
Since the 1990s, it has been recognized that histones
repress early zygotic transcription [12e14], but the
mechanistic basis remains elusive. In this review, we
discuss recent findings on histone control of early
development. We first review recent progress that has
provided new insights into the classical role of histones
as chromatin components in regulating ZGA and cell
cycle remodeling. We then also discuss an unusual,
chromatin-independent signaling mechanism that is
critical for timing the MBT.
Histone supply and ZGA regulation
In several species with large externally fertilized eggs
such as Drosophila, Zebrafish, and Xenopus, large pools of
histones are maternally loaded into the egg prior to
fertilization to support rapid pre-MBT development.
This results in unusually high histone-to-DNA ratios
and excess non-DNA-bound histones. For example, in
Xenopus, a pool of histones sufficient to chromatinize
20,000 genomes is synthesized during oogenesis [15]. In
Zebrafish, the embryo accumulates more than 3000
genomes worth histones by the 1-cell stage [16]. In
Drosophila, zygotic histone null mutant embryos can
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produce w7000 diploid nuclei using maternally provided
histone stores [17]. These excess early histones
are imported into the nucleus, resulting in unusually
high nuclear histone concentrations [16,18]. Nuclear
histone concentrations decrease as the increasing
number of nuclei dilute the maternal pool during the
repeated cleavage divisions [16,18,19].
Histone concentrations regulate key cellular events at
the MBT. In Xenopus embryos, changing the pool size of
histones results in corresponding changes in the timing
of ZGA and cell cycle remodeling [20]. In Zebrafish,
histones compete with key early transcription factors
(TFs) (Figure 2a), such as Pou5f3 and Sox19b for
chromatin binding [16]. These TFs are pioneer factors
that can evict nucleosomes [21,22], suggesting that the
pioneering activity may be important to compete with
the hyper-abundant early histones. In Drosophila, both
over- and under-expression of maternally provided histones
result in corresponding delay and advancement in
ZGA timing and cell cycle remodeling [23]. Together,
these results demonstrate a common theme of histone
regulation of ZGA.
Dynamics of variant histone composition
during the MBT
The so-called canonical core histones, namely H2A,
H2B, H3, H4, and H1, are inserted throughout the
genome during DNA replication and are referred to as
replication-dependent histones. Histone variants have
different amino acid sequences than replicationdependent
histones and are incorporated in specialized
chromatin contexts, including sites of active transcription,
DNA damage, and heterochromatin [6,24,25].
In contrast to the replication-dependent histones,
variant histones are incorporated at specific sites during
other phases of the cell cycle. The histone variants have
distinct transcriptional regulations, PTMs, and chaperones
[26].
Histone variants show dramatic turnover during ZGA
(Figure 2b). For example, the amount of H2Av on
chromatin increases more than two-fold during ZGA in
Drosophila [27]. Similarly, replication-dependent H3 that
predominates in early cell cycles is replaced by variant
histone H3.3 in the final cycles leading up to ZGA [18].
In contrast, species- and early embryo-specific H1
Figure 1
Mid-blastula transition (MBT) and histone dynamics. Upon fertilization, the early embryos of many species, including Drosophila, Zebrafish, and
Xenopus, undergo a developmental transition after a species-specific stereotypical number of cleavage divisions. This transition involves remodeling and
lengthening of the cell cycle and zygotic genome activation (ZGA) characterized by the onset of activation of zygotic genes and establishment of the
mature chromatin state. Histones are maternally deposited into the embryos during oogenesis and are progressively incorporated into DNA, resulting in a
decreasing Histone/DNA ratio. Histones have been implicated in regulating the timing of several critical events of the MBT, including transcription activation,
chromatin maturation, and cell cycle slowing.
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variants predominate before the MBTand are eventually
replaced by replication-dependent H1 in somatic cells in
Drosophila [28], Zebrafish [29,30], and Xenopus [31e33].
In Zebrafish, an oocyte-specific H2Af1o variant supplied
in the early embryo becomes depleted before the ZGA
[34]. Understanding whether the replacement of these
variant histones occurs at specific genomic regions, such
as sites of active transcription and heterochromatin requires
further investigation. It may also be interesting to
determine if distinct variant species are incorporated
into the same nucleosome.
Although histone variants play important roles in
marking specific sites within the chromatin, the functional
relevance of the change of histone variants at the
MBT remains elusive. In Drosophila, H3.3 mutants can
develop normally if provided with replication-dependent
H3 under the control of H3.3’s cis-regulatory elements
[35,36]. Likewise, current research suggests that the loss
of Drosophila H1 variant dBigH1 can be compensated by
replication-dependent H1 [37]. It may be that in
Drosophila the amino acid difference between
replication-dependent and variant histones is less
important than simply having enough of each histone at
the correct stage. However, histone variants have
demonstrable roles in Zebrafish and Xenopus MBT. In
Zebrafish, perturbations to installation of the H2A
variant H2A.Z lead to inappropriate activation or
repression of genes that are marked by H2A.Z containing
placeholder nucleosomes [38]. In Xenopus, H3.3 is
essential for proper gastrulation immediately after the
MBT and cannot be rescued by replication-dependent
Figure 2
Current Opinion in Cell Biology
Histone regulation of ZGA. (a) Excess histones compete with TFs for DNA binding and suppress transcription in early stages. TFs eventually
outcompete histones as histone concentrations decrease in later cycles. (b) The histone composition of chromatin dynamically changes during early
embryogenesis. For example, in Drosophila, incorporation of variant histones H2Av and H3.3 into chromatin increases in the final cleavage divisions
leading up to the MBT. (c) Early chromatin is relatively depleted for histone PTMs. Many histone PTM marks associated with active transcription and gene
silencing increase over the MBT.
Histones in development Shindo et al. 3
www.sciencedirect.com Current Opinion in Cell Biology 2022, 75:102069
H3 [39,40]. Rescue of the H3.3 knock-down by H3/H3.3
chimeric proteins revealed that the H3.3-specific S31
residue is critical for proper development, indicating that
the amino acid differences between replicationdependent
histones and variants do matter in some circumstances.
What determines a specific requirement of
variant histones during early development requires
further study.
Bulk changes in the state of histone PTMs
during the MBT
Given the well-established roles for PTMs in transcription
regulation, it is unsurprising that the genome
acquires many novel PTMs at the onset of ZGA
(Figure 2c). ChIP-chip/seq and more recently
CUT&RUN/CUT&TAG techniques have allowed for
extensive mapping of sites for PTMs over the course of
early development [41e47]. The contributions of the
various histone PTMs are too numerous to discuss fully
here, we encourage the reader to refer to a recent review
[7] for further details. The genome-wide atlas of histone
PTMs has dramatically increased our understanding of
developmental dynamics of histone PTM landscapes as
well as their associations with cis-regulatory elements.
However, the temporal resolution of these analyses is
relatively low compared to the timescale of gene
expression in rapidly developing embryos, and our understanding
about temporal regulation of PTMs and
transcription control remains limited.
Live-imaging probes for chromatin modifications allow
for more precise temporal analysis of the changing PTM
landscape [48]. For example, live-imaging of both
H3K27ac and the elongation form of RNAPol2 using
Fab-based fluorescent probes revealed that acquisition
of H3K27ac precedes the onset of the earliest zygotic
gene transcription in Zebrafish [49]. The effect of
H3K27ac on transcription in the early embryo is global
since injection of the writer (P300) and reader (Brd4) of
H3K27ac results in premature expression of thousands
of genes [50]. Chemical inhibition of P300 and Brd4
abolishes transcription and in turn blocks gastrulation,
suggesting that a gain of H3K27ac is an essential step to
initiate the zygotic developmental program in Zebrafish
[50]. However, mouse embryonic stem cells (mESCs)
do not appear to share this requirement for H3K27ac for
proper transcription. It may be that in mice, the
different developmental program or genome architecture
allows for the functional compensation for loss of
H3K27ac by other features, such as H3K4me1, and
acetylation at other residues [51]. Similarly,
catalytically-dead mutants for H3K4me1 methyltransferase
can result in normal development and transcription
in Drosophila and mESCs, although the
mutants manifest developmental abnormalities under
stress conditions [52,53]. An important open question is
to disentangle the contributions of each PTM and
crosstalk between PTMs to ZGA and development in
different species.
In parallel with the onset of zygotic transcription, heterochromatin
is established during the MBT. Liveimaging
of a fluorescently-labeled H3K9me2 Fab, a
PTM characteristic of constitutive heterochromatin, in
Drosophila showed that bulk levels of H3K9me2 increase
during repeated cleavage division cycles leading up to
the MBT [54]. It also revealed that interphase durations,
which lengthen leading up to the MBT, limit the
extent of H3K9me2 deposition. This indicates that ZGA
and cell cycle slowing are not independent processes at
the MBT, but rather influence each other [54e57].
Together, these works provided quantitative insights
into how bulk histone PTMs change during the MBT.
Integrating the bulk PTM dynamics with chromatin
states at individual loci will be one of the next challenges
for researchers seeking to understand chromatin
control of development.
Emerging roles of histones in cell cycle
control, beyond chromatin regulation
In addition to their roles in transcription and chromatin
regulation, histones have also been shown to control cell
cycle remodeling at the MBT. Given the central role of
histones as core chromatin components, it is tempting to
think that histone control of cell cycle slowing would be
mediated entirely through the action of downstream
transcripts. Indeed, in Drosophila, transcription of the cell
cycle regulator frs responds to changes in the size of the
maternally loaded histone pool [23]. However, in many
contexts histones play additional roles as more than
chromatin components. The antibacterial properties of
histones in vitro were reported, prior to their recognition
as core chromatin components [58,59]. Surprisingly, a
recent study showed that the histone H3-H4 tetramer
has an enzymatic activity to catalyze cupric ion reduction
[60]. New work on the early Drosophila embryo has found
that histone H3 can regulate cell cycle progression independent
of chromatin incorporation [61]. This study
used truncated histones H3 and H4 that retain the Nterminal
tail regions which are the sites of the majority of
histone post-translational modifications but lack the
histone fold domains required for chromatin incorporation.
Expression of H3-tail significantly increased cell
cycle progression and promoted extra divisions before
MBT, indicating that H3-tail that is not incorporated
into chromatin is sufficient to positively regulate the cell
cycle progression. By contrast, H4-tail expression had no
effect on the cell cycle.
In the early embryos, cell cycle remodeling requires the
activation of the checkpoint kinase, Chk1, which phosphorylates
downstream targets to slow and eventually
stop the cell cycle. Canonical substrates for Chk1
include cell cycle regulators, such as Wee1 and Cdc25,
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which directly control the activity of the Cdk1-cyclin B
complex that drives cell cycle progression. Interestingly,
it was reported that Chk1 also phosphorylates the H3tail
[62]. This led to a hypothesis that histone H3 may
outcompete Chk1’s other substrates for Chk1 binding in
the early embryo because of the unusually large amounts
of maternally provided histones. In vitro kinase assays
revealed that phosphorylation of relevant Chk1 substrates,
Cdc25, was reduced by the presence of H3-tail at
physiological concentrations. Measurements of a Chk1
sensor in the living embryos also showed that excess H3tail
decreases Chk1 activity in vivo. Mutation of the Chk1
phosphosite in the endogenous H3 protein advanced cell
cycle slowing. Together, these data indicate that histone
H3 acts as a competitive Chk1 inhibitor independent of
chromatin incorporation. Since Chk1 has not been
observed to interact with other histones than H3, this
competitive inhibition mechanism is H3-specific,
consistent with the observation that H4-tail had no
effect on the cell cycle. Because excess histones become
depleted as the embryo undergoes the repeated cleavage
divisions, this mechanism allows coupling of developmental
progression to the timing of Chk1 activation and
cell cycle remodeling (Figure 3) [61].
In principle, similar competitive inhibition mechanisms
could affect any histone interaction partners, not just
Chk1. Interestingly, it has been shown that histone H3tail
is cleaved in some species and cell types and this
histone clipping is involved in gene expression and
cellular differentiation [63e66]. This could allow H3tail
signaling to be modulated independent of the
amount of histone on chromatin, possibly providing a
broader dynamic range for signaling by free histones.
How and whether extra-chromosomal histones play a
role in other species and cellular contexts is an interesting
area for future study. Together, we propose that
histones should be seen as a multi-faceted molecule that
acts not only as chromatin components but also as regulatory
molecules critical for early development.
Concluding remarks and outlook
In this review, we have discussed the versatile roles for
histones in early development. Some of these include
well-established pathways for chromatin control of
genome accessibility and transcription. However, we
also highlight emerging functions of histones independent
of chromatin incorporation. We have focused on the
Figure 3
Current Opinion in Cell Biology
Role of histone H3 beyond chromatin in the MBT. Cell cycle slowing at the MBT requires the activation of the Chk1 kinase that pauses cell cycle
progression. Given its hyper-abundance, histone H3 acts as a competitive Chk1 inhibitor independent of chromatin association. The reduction in nuclear
H3 concentrations during the cleavage division cycles results in an increase in Chk1 activity, thereby coupling the timing of cell cycle slowing and
developmental progression.
Histones in development Shindo et al. 5
www.sciencedirect.com Current Opinion in Cell Biology 2022, 75:102069
early embryonic stages of the Drosophila, Zebrafish, and
Xenopus model systems, which undergo coordinated cell
cycle slowing and ZGA at the MBT. It remains to be
seen if a similar framework plays a role in other organisms
including mice and humans, in which ZGA is not
coupled to cell cycle slowing. Another key question is if
and how histones contribute to the spatial patterning of
ZGA to regulate differentiation. Finally, given the
numerous cellular processes that are regulated by histones,
a major open question will be to address how the
different histone signals are coordinated in normal
development and if such coordination goes awry in disease.
For example, changes in a histone signal that affects
the cell cycle may indirectly alter transcription
through changing interphase durations that limit the
transcriptional time window; and vice versa, where
changes in transcription may remodel the cell cycle.
Histone biosynthesis and nuclear import may have a
more global impact on cellular physiology than we had
previously recognized because they are common to the
multiple histone pathways. Thus, a major challenge in
the field will be to understand at the systems-level the
mechanisms and principles for histone signal integration
and its physiological consequences.
Author contributions
Conceptualization, Y.S. and A.A.A.; Writing e Original
Draft, Y.S., M.G.B., and A.A.A. Writing e Review &
Editing, Y.S., M.G.B. and A.A.A.
Conflict of interest statement
Nothing declared.
Acknowledgments
We apologize to those whose work we were unable to cite owing to space
limitations. This work was supported by bioMT through NIH NIGMS
grant P20-GM113132, JSPS Overseas Research Fellowships, the Postdoctoral
Fellowship from The Uehara Memorial Foundation, and the
Osamu Hayaishi Memorial Scholarship for Study Abroad.
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8 Cell Nucleus
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