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Control of plant cell differentiation by histone
modification and DNA methylation
Momoko Ikeuchi, Akira Iwase and Keiko Sugimoto
How cells differentiate and acquire diverse arrays of
determined states in multicellular organisms is a fundamental
and yet unanswered question in biology. Molecular genetic
studies over the last few decades have identified many
transcriptional regulators that activate or repress gene
expression to promote cell differentiation in plant development.
What has recently emerged as an additional important
regulatory layer is the control at the epigenetic level by which
locus-specific DNA methylation and histone modification alter
the chromatin state and limit the expression of key
developmental regulators to specific windows of time and
space. Accumulating evidence suggests that histone
acetylation is commonly linked with active transcription and
this mechanism is adopted to control sequential progression of
cell differentiation. Histone H3 trimethylation at lysine 27 and
DNA methylation are both associated with gene repression,
and these mechanisms are often utilised to promote and/or
maintain the differentiated status of plant cells.
Address
RIKEN Center for Sustainable Resource Science, 1-7-22 Suehiro-cho,
Tsurumi, Yokohama, Kanagawa 230-0045, Japan
Corresponding author: Sugimoto, Keiko ([email protected])
Current Opinion in Plant Biology 2015, 28:60–67
This review comes from a themed issue on Cell biology
Edited by Hiroo Fukuda and Zhenbiao Yang
mechanical injuries or hormonal stimuli, undergo cellular
reprogramming to regenerate new tissues or organs [3].
Given that each differentiation step entails global
changes in gene expression, transcription factors have
instructive roles in cellular differentiation and reprogramming. Indeed, recent studies have greatly advanced our
understanding of how key developmental regulators govern a cascade of transcriptional networks to control cell
differentiation and reprogramming [3–6].
Epigenetic modifications refer to mitotically heritable
changes in chromatin without making changes in DNA
sequences and well-characterised examples include DNA
methylation and histone modification. These epigenetic
modifications alter the chromatin environment where
transcription factors and basic transcription machinery
are in play, and influence target gene expression positively or negatively. Earlier studies uncovered vital roles of
epigenetic regulation in controlling key developmental
transitions, that is, embryonic-to-vegetative and vegetative-to-reproductive growth phases [7–9]. In addition,
accumulating evidence implicates epigenetic modifications in the control of cellular differentiation at broader
stages of plant development. In this review we discuss
emerging concepts on the epigenetic regulation of cellular differentiation and reprogramming. Epigenetic regulations governed by other mechanisms such as non-coding
RNA have been recently reviewed in other articles
[10,11], hence we focus our attention on the role of
histone modification and DNA methylation in this article.
http://dx.doi.org/10.1016/j.pbi.2015.09.004
1369-5266/# 2015 Elsevier Ltd. All rights reserved.
Introduction
Cellular differentiation is a sequential process by which
cells that derive from pluripotent stem cells gradually lose
their fate options and acquire a certain determined state.
In plant shoots, for example, stem cells in the shoot apical
meristem (SAM) first give rise to organ founder cells
which subsequently differentiate into leaves or stems
[1]. Cells that have acquired the leaf identity differentiate
into epidermis, ground tissue or vascular tissues, and
many of these cells undergo further specification to gain
terminally differentiated state, for instance, pavement
cells, trichomes and guard cells in the leaf epidermis
[2]. Mature plant organs are also known to maintain a
group of relatively undifferentiated cells, which upon
Current Opinion in Plant Biology 2015, 28:60–67
Histone acetylation in cellular differentiation
Acetylation of the lysine residues within the N-terminal
tail of histones brings the chromatin into a more relaxed
state and often promotes gene expression [12]. The level
of histone acetylation is modulated by counteracting
enzymes called histone acetyltransferases (HATs) and
histone deacetylases (HDACs) that incorporate and remove acetyl groups, respectively. In Arabidopsis 13 HAT
genes and 18 HDACs have been described [13], and
recent studies have shown their key roles in cellular
differentiation. In the Arabidopsis root apical meristem
(RAM), histone acetylation level is highest in mitotically
dividing cells and subsequently drops as cells transit to
differentiate [14]. High histone acetylation is important
to maintain the meristematic activity as mutants in the
HAT complex subunits GENERAL CONTROL NONDEREPRESSIBLE 5 (GCN5) and TRANSCRIPTIONAL ADAPTOR 2B (ADA2b) have shorter roots with
smaller RAM [15]. Conversely, pharmacological inhibition of HDAC activity by Trichostatin A delays cell
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Epigenetic control of cell differentiation in plants Ikeuchi, Iwase and Sugimoto 61
Figure 1
(a)
promotion of
cell differentiation
HDAC
(b)
maintenance of
cell differentiation
PRC2
HAT
WIND3
LEC2
HDA19
TPL
WOX5
CDF4
leaf
guard cell
BP, KNAT2
PRC2
maintenance of
stem cell fate
PRC2
PRC2
?
PRC2
AS1 AS2
promotion of
cell proliferation
maintenance of
cell differentiation
repression of
meristem cell fate
FAMA RBR1
SPCH, MUTE
shoot meristem
(c)
suppression of
cell proliferation
histone acetylation
histone deacetylation
H3K27me3
CYCD4, APC10
DNA methylation
Current Opinion in Plant Biology
Epigenetic regulation of cellular differentiation. (a) At the Arabidopsis root meristem, histone acetylation levels are higher in mitotically dividing cells
compared to post-mitotic differentiating cells. In the columella stem cells, WOX5 recruits HDA19 via its interaction with TPL and represses a
differentiation-inducing factor CDF4 to maintain the stem cell fate. (b) In the Arabidopsis leaves the AS1-AS2 complex maintains the leaf fate by
repressing meristem regulators, BP and KNAT2, through the recruitment of PRC2. In mature guard cells PRC2 represses key determinants of the
precursor fate, SPCH and MUTE, to prevent reinitiation of stomata differentiation. FAMA-RBR may recruit PRC2 to these target loci. (c) In
developing maize leaves, DNA methylation levels increase at the loci of several cell cycle regulators, CYCD4 and APC10, as cells switch from
proliferation to differentiation. Correspondingly, the level of these transcripts decreases in differentiating cells.
differentiation [14], suggesting that controlling the level
of histone acetylation is fundamental for the timely
transition into differentiation (Figure 1a).
The WUSCHEL (WUS) and its close homologs
WUSCHEL-RELATED HOMEOBOX (WOX) transcription factors are the key determinants of stem cell
niche in SAM and RAM, respectively [16,17]. Pi et al.
(2015) have recently reported that WOX5 is transcribed in
the quiescent center cells and moves to adjacent columella stem cells where it represses a differentiationinducing factor CYCLING DOF FACTOR 4 (CDF4)
to keep stem cells undifferentiated [18] (Figure 1a).
Interestingly, WOX5 recruits HDA19 to the CDF4 locus
through its interaction with a co-repressor TOPLESS
(TPL) and suppresses CDF4 expression by deacetylating
histones. The WOX5-mediated deacetylation and CDF4
repression appear to be highly dynamic as this repression
is already abolished after a single round of stem cell
division to allow CDF4 expression in columella cells
[18]. Given that WUS also interacts with TPL [19],
the WUS/WOX-TPL-dependent recruitment of HDACs
might be a general mechanism to maintain stem cell fate
in both shoots and roots.
recent studies have shown that some of auxin-mediated
transcriptional outputs are mediated by histone acetylation and deacetylation. Auxin-responsive genes contain
the AuxRE motif in their promoter sequences that is
bound by auxin response factors (ARFs) and their interacting partners Aux/IAA [21]. In the absence of auxin,
Aux/IAA forms a protein complex with TPL which then
recruits HDA19 to repress ARF-driven gene expression
[22]. As cellular auxin levels increase, Aux/IAA is degraded by the 26S proteosome via the SCFTIR1 pathway, thus
freeing ARF transcription factors to activate target gene
expression [23]. A new study by Weiste and Droge-Laser
(2014) has shown that for a subset of auxin-response genes,
the ARF-mediated transcription is further enhanced
through the GCN5-mediated histone acetylation [24].
The GCN5 complex is recruited to these ARF target
genes by group S1 bZIP transcription factors that recognise the G-box related cis-elements (GRE motif) in their
promoter sequences. Developmental roles of this elegant
epigenetic switch have yet to be elucidated but it would be
interesting to see how this mechanism controls auxindependent cell differentiation and other auxin-mediated
developmental transitions.
Histone methylation in cellular differentiation
The plant hormone auxin forms concentration gradients
along plant bodies, thereby providing positional cues to
promote cell proliferation and differentiation [20]. Several
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Several lysine residues in the N-terminal tails of Histone
H3 can be methylated and affect gene expression either
positively or negatively, depending on the position and
Current Opinion in Plant Biology 2015, 28:60–67
62 Cell biology
number of methyl groups added to each lysine residue.
Trimethylation of Histone H3 at lysine 4 (H3K4me3) is
typically associated with active gene expression while
trimethylation at lysine 27 (H3K27me3) is linked with
gene repression [25,26]. Several methyltransferases that
undertake H3K4me3 have been identified and SET DOMAIN GROUP 2 (SDG2) is responsible for H3K4me3 in
vast majority of genes [27]. Loss-of-function mutants in
SDG2 display pleiotropic developmental phenotypes and
some of these defects, such as reduced leaf and root
growth, are linked with impaired cell differentiation
[27–29]. ARABIDOPSIS TRITHORAX 1 (ATX1)-mediated H3K4me3 has been implicated in the control of
flower development [30,31] and recent studies have uncovered its additional function in the establishment of
organ polarity and root development [32,33]. These observations thus suggest that both SDG2 and ATX1 might
play broad regulatory roles in cellular differentiation.
The H3K27me3 mark is incorporated by a Polycomb
group (PcG) protein complex called POLYCOMB REPRESSIVE COMPLEX2 (PRC2), which together with
PRC1 establishes and maintains the repressive chromatin
state [9,34–37]. As in animals, plant PRC2 is composed of
four subunits and three different forms of PRC2 function
at different developmental stages [38]. The H3K27me3
mark is enriched in genes with tissue-specific expression
profiles [39], and differential methylation patterns between shoot apices and leaves are associated with tissuespecific gene expression [34], suggesting the functional
importance of PcG-mediated gene repression in cellular
differentiation. Several lines of evidence indeed demonstrate that PcG-dependent gene repression is pivotal in
preventing the re-acquisition of stem cell fate in determinate lateral organs in shoots. The KNOTTED-1 like
homeobox class I (KNOXI) genes such as SHOOT MERISTEMLESS (STM), BREVIPEDICELLUS (BP) and
KNOTTED-LIKE FROM ARABIDOPSIS THALIANA 2
(KNAT2) establish and maintain SAM in both monocot
and dicot plants [40]. A study by Lodha et al. (2013)
demonstrated that ASYMMETRIC LEAVES 1 (AS1)
and AS2 recruit PRC2 to the KNOXI genes to repress
their expression outside the meristem [41] (Figure 1b).
When this recruitment is abolished, as found in the maize
mutant rough sheath 2 (rs2) defective in the maize AS1
homolog, KNOX genes are ectopically expressed in developing leaves [42]. Similarly, Arabidopsis PRC1
mutants atring1a atring1b misexpress KNOX1 genes and
develop ectopic SAM in leaves [43]. These results therefore highlight how PcG-mediated histone methylation
prevents attainment of stem cell fate in lateral organs.
PcG-dependent suppression of WUS, which also acts as a
stem cell regulator in flowers, is pivotal for the timely
termination of stem cell activity in floral meristems that
exhibit determinate growth [44]. A floral homeotic regulator AGAMOUS (AG) plays dual roles in this repression
Current Opinion in Plant Biology 2015, 28:60–67
and at an early stage AG first recruits PcG to the WUS
locus to repress its expression [45]. At later stages AG in
turn targets the KNUCKLE (KNU) locus and activates its
expression by competing off PcG that shares the same cisregulatory elements in the KNU promoter [46,47]. Interestingly, H3K27me3 marks at KNU are diluted after
two rounds of cell division to allow the KNU expression
and consequently to shut down the WUS expression
completely [47].
PcG-mediated repression is also required for the maintenance of cellular differentiation in some lineage-committed cells. During stomata development precursor cells
undergo scheduled asymmetric division, fate change and
symmetric division to generate a pair of guard cells [48].
Each step of these sequential differentiation processes is
governed by the bHLH transcription factors SPEECHLESS (SPCH), MUTE and FAMA [49–51]. Two recent
studies have reported that the final differentiated status of
stomata requires active maintenance and failure in this
leads to the reiteration of stomata differentiation within
already existing guard cells. Lee et al. (2014) discovered
that the expression of FAMA-GREEN FLUORESCENT PROTEIN (GFP) fusion protein from its own
promoter causes the ‘stomata-in-stomata’ phenotype
[52]. This phenotype is associated with the heterochronic expression of SPCH and MUTE, which are normally
suppressed by PRC2 at late stages of wild-type stomata
development. The authors further showed that the stomata-in-stomata phenotype can be rescued by overexpressing a subunit of PRC2, CURLY LEAF (CLF),
suggesting that PRC2-dependent suppression of SPCH
and MUTE prevents the reinitiation of stomata differentiation. Matos et al. (2014) found that FAMA interacts
with RETINOBLASTOMA-RELATED (RBR) via a
canonical RBR binding motif (LxCxE) and amino acid
substitutions in this motif cause strong stomata-in-stomata phenotypes [53]. These phenotypes are also accompanied by the ectopic expression of several early stomata
regulators including SPCH and MUTE. Interestingly, ectopic expression of SPCH alone does not mimic the
stomata-in-stomata phenotypes, suggesting that FAMARBR controls gene expression more broadly. Combined
with previous results suggesting tight links between RBR
and PRC2 [54], one plausible hypothesis would be that
FAMA-RBR recruits PRC2 to target loci to block the
reversion of terminal differentiated state in guard cells
(Figure 1b).
An important question is whether other cell lineages also
require similar mechanisms to maintain the differentiated
state, and our recent study indeed demonstrates the
requirement of PcG-mediated gene repression to prevent
reprogramming of fully differentiated root cells [55].
The null PRC2 mutants, such as fie, clf-28 swn-7 and emf23 vrn2-1 [8,9], initially develop relatively normal roots
and, for instance, form root hairs indistinguishable from
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Epigenetic control of cell differentiation in plants Ikeuchi, Iwase and Sugimoto 63
Histone methylation in cellular
reprogramming
Figure 2
PcG-mediated gene repression plays important roles during cellular reprogramming in in vitro tissue culture.
Arabidopsis shoot or root explants form callus when
incubated on the auxin-rich callus inducing media
(CIM) [59], and this process is governed by a genetic
pathway underlying lateral root development [60,61].
Interestingly, PRC2 is required for callus formation from
leaf explants but not from roots [62], suggesting that
repressing leaf traits is the prerequisite for callus formation from leaves. The leaf to callus transition is accompanied by the acquisition of H3K27me3 at 186 genes, some
of which encode known regulators of leaf development
such as SAWTOOTH 1 (SAW1). This transition is also
characterised by the loss of H3K27me3 at 434 genes
including those that encode auxin regulators such as
GH3.2. These observations support the idea that the leaf
to callus transition requires both the suppression of leaf
identity and the activation of auxin pathway (Figure 3a)
although exact targets responsible for this reprogramming
need to be identified in future studies.
(a)
(b)
DNA methylation in cellular differentiation
Current Opinion in Plant Biology
2 PRC2-mediated gene repression is required for the maintenance of
cellular differentiation.
Arabidopsis PRC2 mutants first develop normal root hairs
indistinguishable from wild-type but fail to maintain their differentiated
status, resulting in the callus formation from single root hairs. (a) Wildtype roots (left) and emf2-3 vrn2-1 roots with callus forming hairs
(right). (b) Fluorescence microscopy of DAPI-stained nuclei shows
multicellular root hairs in fie. Bars = 0.5 mm (a), 0.1 mm (b).
wild-type. Later in development these root hairs, which
undergo several rounds of endocycle and increase ploidy
up to 16C [56], revert back to the mitotic cell cycle and
turn into multicellular callus, some of which subsequently
generate somatic embryos (Figure 2). In PRC2 mutants,
several reprogramming regulators, such as WOUND-INDUCED DEDIFFERENTIATION 3 (WIND3) [57], and
embryonic regulators, such as LEAFY COTYLEDON 2
(LEC2) [58], are ectopically expressed, and their overexpression phenocopies multicellular root hairs in wildtype plants, indicating that PcG-mediated suppression of
these regulators is essential to maintain the differentiated
state (Figure 1a). This study also reports dedifferentiation
of other root cells, thus demonstrating the general requirement of this epigenetic regulation in roots.
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Methylation of cytosine in DNA maintains genome integrity and regulates gene expression. In plant genomes,
methylated cytosine is found in any sequence context,
that is, CG, CHG and CHH (H = A, C, or T). DNA
methylation in promoter regions generally has repressive
effects on gene expression but how gene body methylation impacts gene expression appears more complex. For
instance, a tissue-specific methylome analysis using Arabidopsis flowers has associated DNA methylation in the
first exon with gene repression but CG methylation in the
following exon with gene activation [63]. The role of
DNA methylation during plant embryogenesis and floral
development is well documented [64,65] but whether it
plays instructive roles in cell proliferation or differentiation remains elusive. A genome-wide study that investigated the developmentally regulated DNA methylation
in maize leaves uncovered remarkable alterations of DNA
methylation patterns as cells transitioned from the proliferative to differentiation stage [66]. This study identified
a subset of cell cycle genes, such as CYCLIN D4 (CYCD4)
and ANAPHASE-PROMOTING COMPLEX 10 (APC10),
which become both de novo DNA methylated and downregulated in differentiating cells (Figure 1c). Whether
these DNA modifications are causal for cell differentiation needs to be further explored, but these observations
may add another layer of epigenetic regulation in the
control of cell differentiation.
A recent study by Yamamuro et al. (2014) provides evidence that the expression of key regulators in stomata
differentiation is controlled by DNA methylation [67].
Genes targeted by DNA methylation include EPIDERMAL PATTERNING FACTOR 2 (EPF2) which encodes a
Current Opinion in Plant Biology 2015, 28:60–67
64 Cell biology
Figure 3
(a)
callus formation
CIM
repression of leaf cell fate
PRC2
SAW1
SAW1
promotion of auxin signalling
PRC2
GH3.2
GH3.2
shoot
regeneration
(b)
CIM
SIM
MET1
WUS
promotion of auxin signalling
MET1
ARF3
DNA methylation in cellular reprogramming
Stabilised gene repression mediated by DNA methylation contributes to the maintenance of cellular identity in
normal plant development but it interferes with shoot
regeneration from Arabidopsis root explants. Mutants
defective in DNA METHYLTRANSFERASE1
(MET1) display enhanced efficiency of shoot regeneration on shoot inducing media (SIM), and this phenotype
is associated with accelerated WUS induction [69]. The
WUS locus is marked with DNA methylation in wild-type
root explants but its methylation levels decrease after
transfer to SIM to allow its expression. In addition, many
auxin signaling regulators such as AUXIN RESPONSE
FACTOR3 (ARF3) are repressed by MET1-dependent
DNA methylation and released from this repression on
SIM to permit their expression and thus shoot regeneration (Figure 3b).
Conclusions and future perspectives
promotion of shoot meristem formation
WUS
peptide hormone responsible for stomata patterning.
DNA demethylation mediated by REPRESSOR OF
SILENCING 1 (ROS1), DEMETER-LIKE 2 (DML2)
and DML39 is required for the correct EPF2 expression
and thus patterning of stomata cells in Arabidopsis leaves.
DNA methylation also regulates the expression of SPCH
and FAMA, both of which are methylated de novo under
low humidity conditions where it is beneficial for plants to
make less stomata [68].
ARF3
H3K27me3
DNA methylation
Current Opinion in Plant Biology
Epigenetic regulation of cellular reprogramming. (a) Incubation of
Arabidopsis leaf explants on auxin-rich callus inducing media (CIM)
promotes callus formation. PRC2 is required for this process to
incorporate H3K27me3 marks to leaf development genes such as
SAW1 and thereby repress leaf cell fate. The leaf to callus transition is
also associated with the loss of H3K27me3 at several auxin signaling
genes such as GH3.2. (b) Successive incubation of Arabidopsis root
explants on CIM and shoot inducing media (SIM) induces DNA
demethylation of WUS, a key stem cell regulator of SAM, as well as
auxin signal components such as ARF3.
Current Opinion in Plant Biology 2015, 28:60–67
Recent research has made substantial progress in unveiling how epigenetic regulation is intertwined with genetic
transcriptional regulation to assist faithful progression of
plant development. Cellular differentiation is instructed
by the action of key transcriptional regulators, many of
which are under epigenetic control to spatially and temporally regulate their expression during development. It
is also now evident that some of these transcription factors
recruit or evict epigenetic regulators to activate or repress
target gene expression through locus-specific chromatin
modifications. These multi-layered mechanisms that link
epigenetic and genetic regulations likely serve as a safeguard to control developmental stage-specific gene expression. The discoveries that these mechanisms are still
needed even after cells fully differentiate highlight the
striking plasticity of plant cells.
Epigenomic studies in Arabidopsis and maize show that
both histone modification and DNA methylation profiles
undergo dynamic genome-wide changes as cells differentiate. These studies also highlight the complexity of
these modifications, and one of the major challenges in
future studies will be to understand how plant cells
decode various types of epigenetic modifications and
translate these signals into single transcriptional outputs.
The answer to these questions may come from more
advanced methodology for studying chromatin structures,
for example using and Hi-C seq [70] and ATAC-seq [71],
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Epigenetic control of cell differentiation in plants Ikeuchi, Iwase and Sugimoto 65
by which various combinations of epigenetic modifications can be linked to the three-dimensional structure and
overall accessibility of chromatin. Following epigenetic
changes at higher cellular resolutions, for example, using
single cells or single cell types in plant tissues, will also be
a key to untangle the causal relationships between chromatin modification and cell differentiation.
Acknowledgements
We thank Bart Rymen, Anna Franciosini, Natalie Clark and Lewis Watt for
providing comments on the manuscript. Research in the authors’ laboratory
on the topic of this review is supported by a grant from Scientific
Technique Research Promotion Program for Agriculture, Forestry,
Fisheries and Food Industry and grants from the Ministry of Education,
Culture, Sports and Technology of Japan to MI (15K18564), AI (15K18565)
and to KS (26291064, 15H05961). MI is a recipient of the RIKEN Special
Postdoctoral Researcher Program.
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