Download Epigenetic inheritance of expression states in plant development

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Epigenetic inheritance of expression states in plant
development: the role of Polycomb group proteins
Claudia Köhler* and Ueli Grossniklaus†
Polycomb group (PcG) proteins maintain a repressed state of
gene expression over many cell divisions. The recent
characterisation of several PcG proteins from plants revealed a
remarkable structural and functional conservation of PcG
proteins between different kingdoms. In both plants and
animals, homeotic genes are among the target genes of PcG
complexes, although the structure of these genes is not
conserved. However, not all PcG proteins identified in animals
are present in plants. Furthermore it becomes clear that PcGmediated repression in plants is more transient compared with
the long-lasting effects in animals. This may be related to the
absence of PcG proteins thought to be involved in long-term
maintenance of PcG repression, suggesting that the
mechanisms underlying PcG-mediated repression differ
between plants and animals.
Addresses
Institute of Plant Biology, University of Zürich, Zollikerstrasse 107,
CH-8008 Zürich, Switzerland
*e-mail: [email protected]
† e-mail: [email protected]
Current Opinion in Cell Biology 2002, 14:773–779
0955-0674/02/$ — see front matter
© 2002 Elsevier Science Ltd. All rights reserved.
DOI 10.1016/S0955-0674(02)00394-0
Abbreviations
AG
AGAMOUS
CLF
CURLY LEAF
EMF
EMBRYONIC FLOWERING
ESC
Extra sex combs
E(Z)
Enhancer of zeste
FLC
FLOWERING LOCUS C
FIE
FERTILISATION-INDEPENDENT ENDOSPERM
FIS
FERTILISATION-INDEPENDENT SEED
HDAC
HISTONE DEACETYLASE
PCG
Polycomb group
TRXG
trithorax group
MEA
MEDEA
PRC1
Polycomb repressive complex 1
SU(Z)12 Suppressor of zeste12
VRN2
VERNALISATION2
Introduction
Polycomb group (PcG) genes were initially discovered in
Drosophila melanogaster through the analysis of mutants
exhibiting posterior transformations of body segments.
The mutant phenotypes suggested that PcG genes keep
homeotic genes in a transcriptionally repressed state. Once
the spatial pattern of homeotic gene expression in early
embryos is established through the activity of the segmentation genes, PcG proteins maintain this expression
pattern throughout the remainder of development [1]. By
contrast, proteins of the trithorax group (trxG) are required
to maintain homeotic genes in a transcriptionally active
state [1]. Many genes of the trxG family were identified as
suppressors of mutations in PcG genes. Therefore, it was
hypothesised that both classes of genes have opposing
functions [2]. However, it was shown that some PcG genes
also act as transcriptional activators, suggesting that the
initial classification of PcG genes as repressors and trxG
genes as activators may be not generally applicable [3].
PcG and trxG genes, which stably maintain gene expression
established by other regulators, form a model system to
study the cellular memory of transcriptional states.
PcG and trxG proteins are generally thought to control
higher-order chromatin organisation. Both PcG and trxG
proteins form high-molecular-weight complexes, which can
bind to specific chromosomal response elements [1,4].
However, no DNA consensus sequence of such elements
has yet been defined [5]. It is still unclear how PcG and
trxG complexes bound to their target genes can maintain
active or repressed states of gene expression through
mitosis [4].
To date, the molecular structure of 15 fly PcG proteins has
been identified. They belong to diverse structural classes.
Homologues of the fly PcG genes have been cloned from
many different organisms. In mammals, PcG proteins also
regulate expression of homeobox genes, and mutations in
PcG and trxG genes cause axial and limb transformations
[6]. Furthermore, PcG and trxG genes regulate cell proliferation, and their misexpression is correlated with the
development of various cancers [7,8]. In Caenorhabditis
elegans, PcG genes are key mediators of transcriptional
repression in the germline, and mutations in these genes
cause a maternal-effect sterile phenotype [9]. Recent work
in plants shows that PcG genes also play important roles at
various stages of the plant life cycle [10]. Thus, the exploitation
of transcriptional regulation by PcG proteins to control
development is remarkably conserved during evolution.
In this review, we discuss the structure and function of PcG
proteins in plants in comparison to their animal counterparts. Rather than discussing general aspects of chromatin
remodelling and modification, we focus on the developmental role of PcG genes during the plant life cycle.
CURLY LEAF regulates homeotic gene expression
The first PcG gene characterised in Arabidopsis, CURLY
LEAF (CLF), is similar to Enhancer of zeste [E(z)] from
Drosophila [11] (Figure 1). In addition to some other
conserved domains, CLF and E(Z) share the SET domain,
a conserved region initially found in three Drosophila
proteins, Suppressor of variegation 3-9 [SU(VAR)3-9], E(Z)
and TRX [12,13]. The phenotypes of the clf mutant resemble
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Cell differentiation
Figure 1
E(Z)
MEA
CLF
ESC
FIE
SU(Z)12
FIS2
EMF2
Acidic domain
Cysteine-rich domain
SET domain
200 amino acids
WD repeats
200 amino acids
Structural similarities of PcG proteins in
different species. The conserved structural
elements of the Drosophila proteins E(Z),
ESC and SU(Z)12 were compared with
structural elements of similar Arabidopsis
proteins and are indicated by coloured bars.
E(Z), MEA and CLF contain an acidic domain,
a cysteine-rich domain and a SET domain
[11,15]. ESC and FIE contain seven WD 40
repeats [19]. SU(Z)12, FIS2, EMF2 and
VRN2 contain a zinc finger and a conserved
region named VEFS box (VRN2, EMF2, FIS2
and SU(Z)12). SU(Z)12, EMF2 and VRN2
also contain a conserved basic domain at the
amino terminus [20,31•,34•,36••]. The scale
is indicated.
Basic domain
Zinc finger
VEFS box
200 amino acids
VRN2
Current Opinion in Cell Biology
transgenic plants constitutively expressing the homeotic
MADS-box gene AGAMOUS (AG). Flowers of clf plants
show partial homeotic transformations of sepals and petals
into carpels and stamens, respectively [11]. Expression
analysis suggests that CLF is necessary for the maintenance of AG repression during later stages of development,
and not for the initial specification of the AG expression
domain. Similarly, the E(Z) protein from Drosophila is
necessary to maintain the transcriptional repression of
homeotic genes in the Antennapedia- and bithorax-complexes
(ANT-C and BX-C) [1]. This conservation of PcG function
is particularly striking in view of the fact that homeotic
genes in plants and animals are structurally unrelated and
encode homeobox and MADS-box genes, respectively
[14]. This suggests that evolutionary old regulatory complexes have been recruited for similar processes in both
plants and animals.
In Arabidopsis, CLF seems not to be sufficient for AG
repression, as the CLF mRNA is present in all four whorls
throughout flower development and overlaps with the
AG expression domain in the third and fourth whorls.
Therefore, specificity of CLF repression could involve
other proteins that form a repressive PcG complex with
CLF that is restricted to whorls 1 and 2 [11].
Role of PcG proteins during seed development
A genetic screen for gametophytic mutants showing a
maternal effect led to the identification of the medea (mea)
mutant [15]. Additional alleles of the same gene (FERTILISATION-INDEPENDENT SEED1 [FIS1]), as well as two
other loci (FERTILISATION-INDEPENDENT ENDOSPERM
[FIE]) and FIS2), were identified in screens for mutants
displaying fertilisation-independent seed development
[16–21]. All three fis class mutants exhibit a maternaleffect seed abortion phenotype and initiate endosperm
formation in the absence of fertilisation with variable penetrance. Seeds derived from female gametophytes carrying
a mutation in one of the FIS genes abort, irrespective of
whether the paternal allele is mutant or wild type. The
embryos in aborting seeds are delayed in their development, and overproliferate to form an abnormally large
heart-stage embryo. The endosperm also shows proliferation
defects. In addition, the central cell of fis mutants can start
dividing without a fertilisation signal. Thus, it was suggested
that the primary function of the FIS genes is to regulate
cell proliferation [21,22].
The MEA gene encodes another SET-domain protein
similar to E(Z). It was shown recently that the SET
domain of the SU(VAR)3-9 protein family has histone
methyltransferase activity and methylates Lys9 of histone
H3 [23]; however, to date neither for E(Z) nor its mammalian homologues, EZH1 and EZH2, has a histone methyltransferase activity been detected [24] (see Update). In
Drosophila, the E(Z) protein is found in a 600 kDa protein
complex and directly interacts with the WD40 domain
containing protein Extra sex combs (ESC) [25]. The FIE
protein from Arabidopsis is similar to ESC and was shown
to interact with MEA, as was suggested by the common
mutant phenotypes of mea and fie [26–28]. E(Z) and ESC
are widely conserved and have been shown to interact in
Polycombing development in plants Köhler and Grossniklaus
775
Figure 2
CLF
FIE
AG
?
Flowering
Gametophyte
development
?
?
VRN2
FLC
Before fertilisation
Vernalisation
MEA
CLF
FIE
EMF
FIE
FIS2
???
AG
MEA
FIE
Germination
FIS2
???
After fertilisation
Current Opinion in Cell Biology
A speculative view of PcG complexes throughout the Arabidopsis life
cycle. In Arabidopsis flowers, a putative complex of CLF, FIE and
unknown proteins regulate flower organ development by repressing
AG [11,35]. In the female gametophyte, MEA, FIE and FIS2 inhibit a
precocious proliferation of the central cell by repressing unknown
target genes. It is most likely that the same proteins together regulate
embryo and endosperm proliferation during seed development [26,27].
At the seedling stage, CLF, FIE and EMF2 repress the switch from
vegetative to generative development. Mutants in all three genes
express AG at the seedling stage [11,33,34•]. VRN2, together with
other proteins, also controls the onset of flowering by keeping the floral
inhibitor FLC repressed after vernalisation [36••].
both mammals and C. elegans [29,30•]. Thus, the interaction
between E(Z) and ESC homologues forms the core of an
ancient repressor complex deployed in highly diverged species.
the mea, fie and fis2 mutants and their overlapping expression
patterns suggest that all three proteins are part of one
complex regulating common target genes [26,27]. Because
neither MEA nor FIE interact with FIS2 in yeast twohybrid studies, it is possible that the interaction is transient,
involves other proteins, or that FIS2 is not a component of
the MEA–FIE complex at all [27] (see Update).
The FIS2 protein is similar to the Drosophila Suppressor of
zeste12 (SU[Z]12) protein and is also conserved in vertebrates [31•] (see Update). One characteristic feature of
these proteins is a zinc finger similar to fingers found in
sequence-specific DNA-binding proteins. However, DNAbinding activity has not been reported for either FIS2 or its
homologues. The similarities of the mutant phenotypes of
Role of PcG proteins during floral induction
The transition from vegetative to reproductive development
requires important changes in gene expression, which have
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Cell differentiation
to be tightly regulated. Regulators of flowering time are
endogenous factors, such as plant hormones, and environmental factors, such as photoperiod and temperature
[32,33]. Mutant analyses in Arabidopsis have defined four
major flowering promoting pathways: the photoperiod, the
vernalisation (a period of prolonged exposure to cold
temperature that accelerates flowering), the autonomous,
and the gibberellin pathways. Whereas the first two pathways integrate environmental conditions, the latter two act
largely independently of environmental stimuli but depend
on the developmental competence of the plant [32,33].
The early flowering mutant embryonic flower2 (emf2) does
not produce any rosette leaves but rather initiates small
influorescences whose lateral buds produce only flowers
but no additional inflorescences. Double mutant analysis
demonstrated that the emf2 mutant is epistatic to floweringtime mutants that integrate environmental and endogenous
signals [34•], suggesting a major role for EMF2 in the
repression of reproductive development. The EMF2 protein
shares similarity to the zinc-finger-containing proteins
FIS2 and SU(Z)12. The EMF2 mRNA is expressed
throughout the life cycle of Arabidopsis without any
significant changes during vegetative and reproductive
development. Thus, similar to the situation for CLF, specificity of EMF2 repression does not depend on the time of
EMF2 transcription but most likely involves other proteins
and mechanisms. Likely candidates for interaction partners
of EMF2 are CLF and FIE. The clf mutant shows ectopic
AG expression, as does the emf2 mutant, and it flowers
early, although this phenotype is not as extreme as that of
emf2 [11,34•]. Furthermore, EMF2 antisense transgenic
plants display curled leaves, a characteristic phenotype of
the clf mutant. Finally, a partially complemented fie mutant
starts flowering at the seedling stage, similar to emf2 [35]. A
putative CLF–FIE–EMF2 complex would be analogous
to the MEA–FIE–FIS2 complex, as CLF and EMF are
similar to MEA and FIS2, respectively (Figure 2). As there
are no other genes with similarity to FIE present in the
Arabidopsis genome, it is possible that FIE is a component
of several distinct PcG complexes. This is consistent with
the observation that fie mutants are only viable as heterozygotes while other fis mutants can be made homozygous,
for instance through embryo rescue in culture [18].
VERNALISATION2 (VRN2) is another PcG protein with
similarity to FIS2 and SU(Z)12 and was isolated in a screen
for mutants that do not respond to cold treatment [36••].
Vernalisation usually occurs at the seedling stage but the
transition to flowering happens several weeks later. Thus,
the meristem has to remember this stimulus for several
mitotic divisions, suggesting an epigenetic mechanism
[36••,37]. Vernalisation promotes flowering by downregulating the expression of the MADS-box gene FLOWERING
LOCUS C (FLC), which acts as a strong floral repressor by
negatively regulating the expression of several flowering
promoting genes [38,39]. Several vrn mutants have been
isolated. In these mutants, the mRNA levels of FLC are not
reduced in response to cold temperature, indicating that
they affect regulators of FLC expression [40]. Interestingly,
VRN2 function is only revealed in the presence of mutations leading to an upregulation of FLC expression. Thus,
the VRN2 protein itself is not required for the initial repression
of FLC after cold treatment but rather to keep FLC stably
repressed. VRN2 behaves in a functionally similar way to
PcG proteins in Drosophila and provides insights into the
epigenetic basis of vernalisation. The VRN2 gene is
expressed in the absence of vernalisation and the level of
VRN2 transcript is not altered in response to vernalisation
[36••]. Therefore, VRN2 activity most likely also requires
other factors or mechanisms to establish specificity.
Specificity of PcG action: how does it come
about?
The specific expression patterns of PcG-repressed genes
in Drosophila contrasts with the widespread expression of
PcG proteins [4]. Similar observations were made in plants,
as we pointed out for the overlapping expression patterns
of the PcG proteins CLF and VRN2 and their target genes
AG and FLC, respectively. This implies that highly selective
mechanisms target PcG-mediated repression. One mechanism could be that the regulation of specific subunits of
the multimeric PcG complexes specifies the onset of
repression. Furthermore, it is possible that PcG repression
requires silenced genes as templates, allowing the PcG
complex to lock a previously established expression pattern
in place, whereby active genes are unaffected and silent
genes become stably repressed. In this model, the specificity
of PcG-mediated repression would be determined by the
molecular features of silent chromatin, which allows the
establishment or stabilisation of PcG repressive complexes.
Molecular differences between transcribed and nontranscribed chromatin could be associated proteins, histone
modifications, remodelled nucleosomes and chromatin
compaction. Alternatively, the formation of PcG repressive
complexes on their respective target genes could be the
default state, with features of an actively transcribed gene
inhibiting PcG complex assembly [4]. Finally, the control
of the subcellular localisation or the binding characteristics
by post-translational modifications of PcG proteins could
provide an explanation for their specificity. Such modifications
could be established by certain endogenous signalling
pathways conferring competence to the repressor complexes.
Consistent with this hypothesis is the finding that ESC is
modified by phosphorylation in Drosophila and that the
phosphorylated form preferentially associates with E(Z) [25].
How is the repressive function of PcG complexes
achieved? Given the ubiquitous use of histone modifications
for gene regulation, it is likely that PcG repression in
plants involves histone modifications as well. The correlation
between histone acetylation and gene activation, as well as
histone deacetylation and gene repression, is well established and has also been observed in plants [41–43]. The
Drosophila E(Z)–ESC complex and the corresponding
mammalian EZH2–EED complex have been shown to
Polycombing development in plants Köhler and Grossniklaus
777
interact with RPD3-like histone deacetylases (HDACs)
[44,45••]. RPD3-like HDACs are present in plants and
have been shown to be involved in different developmental
processes [41,43,46]. Considering the highly conserved
interaction between E(Z) and ESC in diverse organisms, it
is possible that transcriptional repression mediated by
plant PcG complexes also involves histone acetylation
and deacetylation.
mammals [1]. The identification of the PcG protein CLF
as repressor of the MADS-box gene AG indicated a widely
conserved function of PcG proteins as repressors of
homeotic genes [11]. Another MADS-box gene, FLC, has
been shown to be regulated by the PcG protein VRN2
[36••]. Interestingly, homeobox genes of animals and
MADS-box genes of plants both function as homeotic
genes, but are structurally not related [14].
Differences between PcG complexes of plants
and animals
In addition to controlling homeotic target genes in development, PcG genes in mammals are also regulators of the
cell cycle. Among others, the INK4a locus of mice, which
encodes the tumour suppressors and cell cycle inhibitors
p16 and p19Arf, is a target gene of the PcG protein BMI-1
[7,8]. In Drosophila and C. elegans, PcG proteins have also
been implicated in the control of cell proliferation.
Similarly, the phenotype of the mea, fie and fis2 mutants,
which produce giant heart-stage embryos and enlarged
endosperm, suggests that target genes regulated by the
MEA–FIE complex are also involved in controlling cell
proliferation. The identification of additional target genes
of PcG proteins in plants will be important to elucidate the
mechanism of PcG action in plants.
Biochemical purification of PcG complexes from
Drosophila embryos and mammalian cells demonstrated
the existence of at least two types of complexes
[25,45••,47]. The first complex is about 600 kDa, contains
E(Z) and ESC, and co-purifies with the RPD3 HDAC
[45••]. It is thought that the E(Z)–ESC complex establishes
a repressed state, before the second class of complexes
takes over to maintain this expression state [4,48•]. The
second complex, Polycomb repressive complex 1 (PRC1), is
a ~3 MDa complex purified from Drosophila embryos [47].
This complex contains the PcG proteins Polyhomeotic,
Polycomb, Posterior sex combs and Sex comb on midleg
[4]. Although no catalytic activity has been defined for any
of the fly PRC1 components, it has been shown that PRC1
blocks chromatin remodelling by the trxG-related SWI/SNF
complex in vitro [47]. However, homology searches did not
reveal coding sequences with similarity to these proteins in
the Arabidopsis genome [49].
In contrast to Drosophila, where PcG-repressed genes
remain repressed once this state is established, PcG
repression in plants can be relieved in response to either
developmental or environmental cues. The repressive
function of EMF2, for instance, inhibits or delays the transition to flowering and is most likely relieved in response
to certain stimuli that promote flowering [34•]. The same
could apply for the action of the MEA–FIE complex. The
mea, fie and fis2 mutants start endosperm development in
the absence of fertilisation, indicating that one function of
this complex is to repress genes before fertilisation and
that repression is relieved by a fertilisation-dependent signal
[16–21]. Therefore, one could assume that, in contrast to
the long-lasting repression mediated by PcG genes in
Drosophila, PcG action in plants is more transient. The idea
is supported by the absence of PcG proteins similar to
those of the PRC1 maintenance complex in plants. Stable
repression of genes could require other proteins or mechanisms that evolved independently in plants and animals.
An attractive hypothesis is that a more transient transcriptional repression in plants is one consequence of the
continuous postembryonic development of their body
plan, which is highly flexible and strongly influenced by
environmental conditions.
Target genes in animals and plants
As mentioned before, PcG genes have been defined as
regulators of homeotic gene expression in Drosophila and
Conclusions
The identification of PcG proteins that are involved in
several developmental processes in plants has revealed that
transcriptional repression using PcG proteins is widely
conserved between different kingdoms. Strikingly, among
the target genes of PcG complexes in plants and animals are
homeotic genes, which are structurally not conserved, and
likely also genes that regulate cell proliferation and growth.
However, there seem to be differences regarding the stability
of PcG-mediated repression between plants and animals.
The characterisation of PcG complexes in plants will,
therefore, be an essential step for understanding the mechanism(s) underlying the cellular ‘memory’ in plants.
Given the recent progress in identifying potential chromatin remodelling factors, additional links between PcG
action and developmental decisions will probably be
uncovered in plants. It will be important to identify
factors regulating PcG protein function at different
stages of plant development and to relate their effects
to the maintenance of gene expression. Finally, the identification of additional target genes for PcG proteins in
plants will be crucial to appreciate PcG action during
plant development.
Update
Recent work has shown that SU(Z)12 is a subunit of the
the E(Z)–ESC complex from Drosophila [50••,51••].
Furthermore, it was demonstrated that this complex contains
a histone methyltransferase activity that methylates Lys9
and Lys27 of histone H3. The human counterpart to the
E(Z)–ESC complex, EZH2–EED, has also been purified
and was shown to have histone methyltransferase activity,
methylating Lys27 of histone H3 [52••].
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Cell differentiation
Acknowledgements
We apologise to our colleagues whose work we could not cite due to space
constraints. C Köhler is an Human Frontier Science Program Fellow, and
our work on Polycomb group proteins is supported by the Kanton of Zürich,
the Swiss National Science Foundation and a Searle Scholarship to
U Grossniklaus.
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