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Seminars in Cell & Developmental Biology 19 (2008) 537–546

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Seminars in Cell & Developmental Biology

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Review

Chromatin dynamics during the plant cell cycle

María de la Paz Sanchez, Elena Caro1, Bénédicte Desvoyes1, Elena Ramirez-Parra1,Crisanto Gutierrez ∗

Centro de Biologia Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Cientificas, Universidad Autonoma de Madrid,Nicolas Cabrera 1, Cantoblanco, 28049 Madrid, Spain

a r t i c l e i n f o

Article history:Available online 30 July 2008

Keywords:Cell division cycleChromatinEpigeneticsCell fate and differentiationPlantArabidopsis

a b s t r a c t

Cell cycle progression depends on a highly regulated series of events of which transcriptional control playsa major role. In addition, during the S-phase not only DNA but chromatin as a whole needs to be faithfullyduplicated. Therefore, both nucleosome dynamics as well as local changes in chromatin organization,including introduction and/or removal of covalent DNA and histone modifications, at genes with a keyrole in cell proliferation, are of primary relevance. Chromatin duplication during the S-phase and thechromosome segregation during mitosis are cell cycle stages critical for maintenance of epigenetic marksor for allowing the daughter products to acquire a distinct epigenetic landscape and, consequently, aunique cell fate decision. These aspects of chromatin dynamics together with the strict coupling of cellproliferation, cell differentiation and post-embryonic organogenesis have a profound impact on plantgrowth, development and response to external signals.

© 2008 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5372. G1 and the G1/S transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5383. S-phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5394. G2 and the endocycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5415. Mitosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5416. Other cell cycle-related processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542

6.1. Cell fate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5426.2. Chromatin-binding proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5426.3. Cell cycle exit and dedifferentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542

7. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543

1. Introduction

In eukaryotes, genomic DNA is complexed with both histonesand non-histone proteins becoming a highly compacted structure,called chromatin. Histones are assembled in a regular manner alongthe chromatin fiber. A basic unit, called nucleosome and consistingof a ∼150 base-pair piece of DNA wrapped around a histone octamercore constituted by two of each histones H2A, H2B, H3 and H4,

∗ Corresponding author. Tel.: +34 911964638.E-mail address: cgutierrez@cbm.uam.es (C. Gutierrez).

1 These authors have contributed equally to this work.

is repeated over the entire genome. Histone H1 associates mainlywith the non-nucleosomal linker DNA and contributes further toDNA packaging.

This repeating nucleosomal organization is far from being amonotonous and static structure. Rather, it represents one ofthe most highly dynamic macromolecular complexes in the cellwith different degrees of condensation which serve to distinguishbetween the transcriptionally active euchromatin from the highlycompacted and largely inactive heterochromatin. This can adoptthe form of constitutive heterochromatin or of facultative hete-rochromatin, whose activity is regulated. In addition, nucleosomalcomponents may differ in their location relative to genetic deter-minants, such as promoters of coding sequences, their nature and

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their covalent modifications. Together, these local characteristics ofchromatin organization have profound consequences on key cel-lular processes involving DNA transactions such as transcriptionalcontrol, DNA replication, DNA repair and recombination. Therefore,the genetic information contained in the DNA sequence is extraor-dinarily enriched by highly specific modifications of certain DNAbases [1] and of nucleosomal histone tails [2], and by the presenceof a variety of histone variants at certain genomic locations [3]. Alto-gether, the modifications that do not entail changes in the genomicDNA code constitute the molecular basis of epigenetic inheritance[4], which ultimately affects the fine-tuning of gene expression.

The accessibility of specific chromatin sites to the transcrip-tional machinery and other chromatin-binding factors is favoredby three major players: chromatin remodeling complexes, DNAmethylation enzymes and histone modification enzymes. Together,they contribute to nucleosome sliding and/or disassembly, incor-poration of histone variants and modification of DNA bases andhistone residues. Histones are one of the most abundant and mosthighly conserved components of the eukaryotic nucleus. Nucleo-somal core histones form heterodimers of H2A–H2B and H3–H4whose N-terminal tails, which are accessible outside the nucleo-some core, possess covalently modified residues, most frequentlylysine residues. These modifications can be acetylation, methyla-tion, phosphorylation, ubiquitylation, sumoylation, carbonylationand glycation [2]. Some histone modifications have been shownto play various roles during cell proliferation (Fig. 1). Differentcombinations of histone modifications confer an extraordinarycombinatorial set of possibilities which, together, are referred toas the histone code. These modifications, and in particular some oftheir combinations whose exact nature is only starting to be under-stood, are of primary relevance for the fine-tuning of transcriptionalregulation. In general, acetylation correlates with transcriptionalactivated genes whereas high methylation is present in transcrip-tionally silent chromatin, although this is highly dependent on themodified residue, as discussed below.

Covalent histone modifications, in many cases reversible, arecarried out by a plethora of highly specific enzymes [2,5]. How-ever, the modified histone tails by themselves are not sufficient toactivate or repress a particular gene. The histone code needs to beinterpreted by effector proteins which specifically recognize certainmodifications and mediate the recruitment of other chromatin-binding proteins with an effect on transcriptional regulation (Fig. 2).Thus, the effector proteins translate the histone code into specificbiological processes with an impact on plant growth and develop-ment (reviewed in Refs. [6–11]). Due to the intimate coupling ofcell proliferation control and plant development [12,13] effects ofchromatin remodeling on cell proliferation also have direct conse-quences on plant development. At the cellular level, these local orglobal changes in chromatin organization are also relevant for cellcycle progression, cell cycle-dependent transcriptional regulationand cell division, the main topic that will be reviewed here.

2. G1 and the G1/S transition

The G1/S transition, both in animals and plants, is character-ized by a burst in transcriptional activation of a large set of genes,largely dependent on the function of the E2F/DP family of tran-scription factors. Retinoblastoma-related protein (RBR), the planthomologue of the Rb protein family, repress E2F/DP-mediated tran-scription [14,15]. This process includes both the direct inhibitionof activator E2F and, as discussed below, the recruitment of chro-matin modifying activities, such as histone deacetylases (HDAC),histone methyltransferases (HMTases) and DNA methyltransferases(Dnmt1) (reviewed in Refs. [16,17]). RBR repression is relieved afterits phosphorylation by CDK/cyclin complexes allowing the G1/S

transition of the cell cycle [13,18,19]. Thus, a large number of genesencoding proteins whose activity is required during S-phase, oreven later in the cell cycle, are activated by E2F/DP. Genome-wideanalysis [20,21] has revealed that genes encoding proteins involvedin chromatin dynamics, including members of the Trithorax com-plex or the chromatin assembly factor 1 (CAF-1), are also bona-fideE2F targets [20,22].

It should be pointed out that studies in plants just start to emergeand most of the information about the implication of RB in chro-matin modification comes from analyses in other organisms. Inhuman cultured cells recruitment of E2F1-3 to their target genepromoters is associated with the appearance of activating markssuch as H3ac and H4ac [23,24]. HDACs remove acetyl groups fromthe tails of core histone in the nucleosome leading to a closed chro-matin conformation that prevents transcription. In mammals, it hasbeen reported that RB interacts directly to HDAC1 [25,26] or in asso-ciation with the Rb-associated protein RbAp48 [27]. In proliferatingcells, this complex is stably bound to E2F target promoters duringearly G1 phase and released at the G1/S transition, thus controllingcell cycle progression [28,29]. These interactions are conserved inplants and have been described in tomato and maize [30–33].

Plant E2F/DP family members have domains highly conservedwith their animal counterparts and maintain the ability for het-erologous interactions, at least in vitro [18,34]. Furthermore, plantE2F regulates the expression of genes at the G1/S transition as wellas that of genes beyond cell cycle regulation. Therefore, given thestructural, and in many aspects also functional homology betweenplant and animal E2F/DP and RBR, it is conceivable that similarinteractions with the chromatin remodeling and histone modifi-cation machinery could also occur in plants. However, the plantE2F/DP/RBR pathway also exhibits some plant-specific features, inparticular considering that some E2F target genes are plant-specific[20,21]. Therefore, it is of primary importance to identify the setof histone modification marks associated with E2F/DP-mediatedtranscriptional regulation during the plant cell cycle and initiationof terminal differentiation. This is also relevant since some histonemarks produce opposite consequences in plants and animals, e.g.H3K9me3 and H4K20me are frequently activating marks of euchro-matin genes in plants and repressing marks in animals ([35,36];Sanchez and Gutierrez, unpublished).

Expression of cell cycle genes can also occur through nucle-osome remodeling, SWI/SNF complexes mainly achieving thisactivity. The catalytic subunits of these complexes are membersof the SNF2 family of DNA-dependent ATPases and it has beenshown that in mammals two of these, BRM and BRG1, interact withRb [37]. In mammalian cells, repressor complexes formed by Rb,SWI/SNF and HDAC control the timing of expression of cyclin E andA which in turn regulate a correct cell cycle progression [38]. How-ever, recently it was demonstrated that interaction with distinctsubset of proteins can have positive or negative effects on prolifer-ation [39]. SWI/SNF complexes are conserved in the plant kingdomand in Arabidopsis, there are four SWI/SNF ATPases [40]. Two ofthese, BRAHMA (BRM) and SPLAYED (SYD) have been studied inmore detail. Arabidopsis BRAHMA (BRM), the homologue of mam-malian SNF2, is highly expressed in proliferating cells [41], andlikely affects the expression of genes relevant for cell cycle progres-sion, although this needs to be demonstrated. Interestingly, this issimilar to the role of mammalian SWI/SNF remodeling complexesin transcriptional control of genes that participate in cell cycle, e.g.enzymes of dNTP metabolism, and cell growth, e.g. c-myc [39,42].However, to date, unlike in mammalian cells, there is no evidence ofinteractions between these proteins and plant RBR. Recently, otherlarge repressive complexes, called dREAM or Myb-MuvB, contain-ing Rb, repressor E2F/DP, RbAp48, Myb proteins and Myb bindingproteins, have been identified in Drosophila, C. elegans and humans

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Fig. 1. Summary of the major covalent histone modifications identified in the N-terminal tail of the four nucleosomal core histones for which a role at different cell cyclestages has been demonstrated. Details of other histone modifications have been reviewed in Ref. [2]. Note that lysines can be mono-, di- or trimethylated and that argininescan be mono- or dimethylated, and in this case, symmetrically or asymmetrically.

Fig. 2. General scheme summarizing the dynamics of histone modifications and how the histone code is translated into a change in transcriptional control relevant for aparticular biological process.

[43–46]. Evidence for the presence of these complexes in plants isstill lacking.

A recent nomenclature defines four groups of histone acetylasesand three groups of histone deacetylases in Arabidopsis [47,48].Unfortunately, detailed experimental analysis of their pattern ofexpression and/or activity is largely lacking. However, microarraydata of highly synchronized Arabidopsis cultured cells are available[49] and the use of the Genevestigator© package [50] has allowedus to draw a number of interesting conclusions. HAG (GCN-like)genes increase their expression from G0 up to early/mid-S-phase,and then stay high (Fig. 3). On the contrary, HAM (MYST-like), HAF(TAFII250-like) and HAC (CBP-like) genes do not show any cell cycleregulated expression. The expression of some RPD3-like histonedeacetylases (HDA and HD2) shows a cell cycle regulated expres-sion with an increase from G1/S up to mid-S-phase (Fig. 3). Thesedata suggest a strong connection between cell proliferation andthe expression of acetyl transferases and deacetylases. It should bepointed out, nevertheless, that in addition to transcriptional regula-tion, some histone modification enzymes, e.g. histone deacetylases,

are also subjected to translational control as revealed by studiesduring the switch to proliferation of sucrose-deprived, arrestedcells [51].

3. S-phase

Chromosome duplication during the S-phase is a crucial stagefor maintenance of epigenetic states as nucleosomes, DNA andhistone modifications have to be transferred correctly, or specifi-cally modified, in the daughter chromatin. During DNA replication,new nucleosomes need to be assembled onto the nascent chro-matin in order to propagate the epigenetic state, a process thatis helped by several histone chaperones. The DNA replicationmachinery recruits the chromatin assembly factor 1 (CAF-1) thatdeposits dimers of acetylated H3 and H4. Then, nucleosome assem-bly protein-1, NAP-1, incorporates H2A/H2B dimers completing thenucleosome core [52].

Results discussed below suggest that dynamic acetylation anddeacetylation may be also relevant for proper S-phase progres-

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Fig. 3. Cell cycle regulated expression of genes encoding histone and DNA modification proteins described in the text. The data were obtained with Arabidopsis culturedcells synchronized by sucrose starvation for 24 h. Samples were prepared at the indicated times (in hours) after release from the sucrose block and processed for microarrayexperiments. Data were collected from publicly available collection of microarray data and have been generated using the Genevestigator© tool package. Gene expressionlevels have been normalized to the ACT2 gene and made relative to the value at the time of sucrose starvation release (0 h). The pattern of histone H4 expression (top left)has been included as a reference for a well-characterized gene up-regulated at the G1/S transition. HAG1-3, histone acetylases 1–3 of the GNAT family; HDT1-4, histonedeacetylases 1–4 of the HD2 family; HDA18-19, histone deacetylases of the RPD3/HDA1 family; SUVH1-2, suv homologue 1–2; LDL3, LSD1 (lysine-specific demethylase1)-like 1; AUR1-3, Aurora kinases 1–3; MET1, DNA methyltransferase 1; CMT3, Chromomethylase 3; FAS1-2, FASCIATA1-2; NAP1, nucleosome associated protein 1; NRP1-2,NAP-related protein 1–2.

sion. Consistent with this observation, cell cycle regulation of theexpression of chromatin modification enzymes, and/or of theiractivity, could be one of the mechanisms contributing to thechanges observed during the cell cycle (Fig. 3). Thus, it has beenshown that RB/E2F in mammalian cells is required for proper cellcycle regulation of Dnmt1 transcription, which may be crucial fortranscriptional control and maintenance of normal DNA methyla-tion patterns [53]. In addition, human RB associates with Dnmt1

through its B and C domains, inhibiting the Dnmt1 methyltrans-ferase activity [54]. A plant homologue of human Dnmt1 has beendescribed in Arabidopsis (MET1) and it plays a major role in main-taining the methylation pattern after DNA replication [55]. MET1 aswell as the DNA methylation maintenance CMT3 genes contain E2Fsites at their promoters [56]. Consistent with this, MET1 expressionis up-regulated at the G1/S transition [49] Fig. 3) and in E2Fa/DPaoverexpressor plants [57]. Recently, it has been shown that RBR, in

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cooperation with MSI1, represses MET1 expression in the centralcell during female gametogenesis [58]. This demonstrates a role ofRBR in activation of imprinted genes, e.g. FIE and FWA, acting inparallel DEMETER, the DNA glycosylase that can demethylate DNA[59,60].

Furthermore, the packaging status of chromatin and perhapsspecific modifications of certain histone residues may be part ofthe mechanism that determines whether a particular origin ofDNA replication becomes active. Consistent with this view, chro-matin complexes have been identified at origins in mammaliancells affecting chromatin structure and gene expression of neighborgenes [61]. The identification of origins in plant cells has been elu-sive so far. However, it is likely that origin activity may also dependon local chromatin organization, and vice versa. In this context, thecatalytic subunit of Arabidopsis DNA polymerase � (ICU2) interactswith LIKE-HETEROCHROMATIN PROTEIN 1/TERMINAL FLOWER2(LHP1/TFL2) and with CURLY LEAF (CLF), a component of PcG com-plexes [62]. Furthermore, weak alleles of ICU2 show homeotictransformations, indicative of specific changes in gene expression.

CAF-1 is a heterotrimeric complex highly conserved duringeukaryotic evolution (reviewed in Ref. [52]). In Arabidopsis, thethree subunits of CAF-1 are encoded by the FASCIATA1 (FAS1), FAS-CIATA2 (FAS2) and MULTICOPY SUPPRESSOR OF IRA1 (MSI1) genes[63–65], which are E2F targets [22]. Loss of function of CAF-1 pro-duces viable plants, although they show severe and pleiotropicdevelopmental abnormalities. fas1 and fas2 mutants are fasciated,having broad and flat stems with altered leaf phyllotaxy, presentdentate and narrow leaves and abnormal flowers. The mutantplants also show defects in the cellular architecture of shoot androot meristems. Thus the expression domains of WUSCHEL (WUS)and SCARECROW (SCR), typical markers of the shoot and root apicalmeristems, respectively, are disorganized [64].

Genome-wide microarray experiments indicate that loss ofCAF-1 also affects transcriptional activation of a subset of genes,mainly involved in S-phase regulation and DNA repair [66]. Thus,G2 DNA damage checkpoint markers genes, directly involvedin homologous recombination present increased expression lev-els in fas mutants [9,67,68]. Curiously, some promoters of genesup-regulated in fas mutants are enriched in typical marks of tran-scriptional activation such as acetylated histones H3 and H4 butthey present a reduction in H3K9me2, an epigenetic mark of hete-rochromatin in plants [9]. These facts suggest that CAF-1 could beinvolved in coordinating DNA replication with chromatin assemblyand the maintenance of appropriate epigenetic marks.

CAF-1 is also necessary for maintaining the correct pattern ofheterochromatin silencing, although the molecular links betweenCAF-1 and the transcriptional silencing mechanisms still remainunknown. Thus, Arabidopsis fas and msi mutants have reduced het-erochromatin content and dispersed pericentromeric DNA. Alsogenomic DNA of fas mutants presents hipersensitivity to DNaseIdigestion, suggesting that loss of CAF-1 provokes a less com-pacted chromatin conformation [66,67]. However, transcriptionalsilencing on some telomeric and pericentromeric heterochromatinregions, as well as DNA methylation pattern is maintained in fasmutants [66] and slight transcriptional activation of heterochro-matin remains reduced to some local heterochromatic regions [69].

Changes in histone acetylation have been reported to occurduring S-phase, although the patterns are species-specific. Thus,in Arabidopsis, a DNA replication-linked increase in H3K18ac andH4K16ac, but not in other histone residues, occur [70]. Likewise,H4K5ac, H4K12ac and H4K16ac in the field bean [71]; H4K5ac,H4K8ac and H4K12 in barley [72], and H4K5ac in onion [73],also increase in S-phase. These changes could correlate with theincrease in histone acetylase and deacetylase activity detected inmaize [74].

4. G2 and the endocycle

Cells are normally committed to divide once they have dupli-cated their genetic material, except when they enter the endocycleprogram whereby repeated rounds of chromosome duplicationoccurs in the absence of mitosis, a frequent process occurringduring plant cell differentiation. Activation of S-phase and G2checkpoints end up in G2 arrest. One of the conditions leading toG2 checkpoint activation is the alteration of chromatin organiza-tion, which can be the consequence of the misfunction of multiplepathways.

DNA replication stress induced by inhibition of DNA replicationleads to G2 checkpoint activation, G2 arrest and increase in his-tone H2AX phosphorylation and �-H2AX foci [75,76]. Interestingly,loss of CAF-1 in fas1 mutants phenocopies the G2 checkpoint activa-tion and H2AX phosphorylation pattern [9,67,68,77]. Moreover, fas1mutants are hypersensitive to DNA replication stress and double-strand break-inducing treatments. However, loss of CAF-1, whichlikely leads to an aberrant DNA replication-associated nucleosomedeposition, does not lead in plant cells to permanent G2 arrest andcell death, as it occurs in animal cells [78–83]. Instead, constitu-tive activation of the G2 checkpoint response is associated withpremature and systemic triggering of the endocycle program [9]. Itshould be kept in mind that endoreplication is a very common pro-cess in plants, frequently associated with differentiation pathways.Therefore, plants may have taken advantage of this evolutionarytrend to cope with chromatin defects during development and post-embryonic growth. Mutants in the MSI1 subunit of CAF-1 also havedevelopmental defects, although in this case they can be due, atleast in part, to the interaction of MSI with the retinoblastomaprotein [31] or the Polycomb complexes [84].

Altered function of other histone chaperones during S-phasealso has cell cycle effects. Arabidopsis contains several NAP1 andtwo NRP (NAP1-related protein) involved in depositing H2A–H2Bdimers after CAF-1 function. Mutants in these chaperones showincreased G2 arrest, indicative of their role in cell proliferation con-trol [85,86], although the molecular basis for these defects remainsunknown. In addition to alterations in histone H3 and H2A/H2Bdynamics, specific histone modifications have direct effects onthe cell cycle progression. HUB1 (Histone mono-ubiquitination1) is a RING E3 ligase which monoubiquitinates histone H2B.The mutant allele hub1-1, also known as ang4-1, shows extendedcell cycle duration, mis-expression of G2/M marker genes andpremature switch to the endocycle program [87]. In particular,among the genes down-regulated in the hub1-1 plants it is strik-ing the presence of several cyclin A and cyclin B genes, 3 CDKBgenes and >25 kinesins, kinesin-like proteins and factors requiredfor microtubule dynamics, consistent with the G2/M progressionphenotype. In this context, it is worth noting that H2B monoubiq-uitination by BRE1, the yeast and human HUB1 homologue, hasbeen shown to be required for trimethylation of H3K4 at cod-ing sequences of genes that need to be activated during the G2phase [88–91].

Together, all these data reveal a relevant cross-talk between his-tone deposition, histone modification and the control of S-phaseprogression, G2 checkpoint activation and the switch to the endo-cycle program.

5. Mitosis

Apart from the small and regional variations in the condensationstate of chromatin during interphase discussed above, it is at theonset of mitosis when all chromosomes become highly condensedto facilitate accurate segregation of the genetic material to daugh-ter cells. Phosphorylation of H3S10 starts early in prophase and

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continues until telophase [92]. H3S10ph is a histone modificationconserved across eukaryotes, including animals [93–96], protozoa[97] and plants [92]. This suggests that the dynamic process ofH3S10ph in mitosis, associated with chromosome condensation,is conserved during evolution of both unicellular and multicel-lular organisms. In addition, H3 phosphorylation at residues T3,T11 and S28 has been also detected [98]. However, H3T3ph andH3T11ph occur only in mitosis [98] whereas H3S10ph and H3S28phare detected in mitosis and meiosis [92,99–101]. The consequencesof this H3 phosphorylation code remain to be fully defined.

Many kinases appear to be involved in histone H3 phosphoryla-tion, suggesting that it might be a stimulus- or cell type-dependentprocess. Histone H3 phosphorylation at S10 is carried out inmammalian cells by multiple kinases, including mitogen andstress-activated protein kinases 1 and 2 (MSK1 and MSK2), cAMP-dependent protein kinase A (PKA), NIMA kinase, Aurora B kinase,ribosomal S6 kinase 2 (RSK2), and IkB kinase a (IKKa) (reviewed byRef. [102]). The Arabidopsis genome contains three AURORA (AUR1to AUR3) kinases [103] which all show high expression levels inactively proliferating cells, supporting their potential role in H3phosphorylation. Moreover, AUR genes are more highly expressedin mitosis (Fig. 3) and H3 is a good substrate in vitro for AUR kinases[103–105]. Homologues of the Aspergilus nidulans NIMA kinase,which phosphorylates H3S10 [106], are present in several plantspecies [98,107–109]. However, their residue specificity has notbeen determined. The TOUSLED (TSL) kinase expression is constantduring the cell cycle, but its activity increases in late G2/M, M andearly G1. H3 is among the known substrates of TSL kinase [110],suggesting that TSL and AUR kinases may compete or act coordi-nately in H3 phosphorylation, although other reports indicate thatTSL does not have a role in H3S10 phosphorylation [111].

Histone H3 phosphorylation seems to play a role also in tran-scriptional control. Recent studies have demonstrated a cross-talkbetween the different histone modifications (reviewed by Ref.[102]). Thus, H3S10ph can enhance H3K14ac [112,113], abolishH3K9ac [114] and inhibit H3K9me [115]. Conversely, H3K9meinterferes with H3S10ph [115]. Histone deacetylation is fre-quently associated with transcriptional repression and is also likelyrequired for correct packaging of nucleosomes into metaphasechromosomes. Thus, a loss of acetylation of all histones wasobserved in M-arrested cells. In particular, H3K18ac, H3K23ac,H4K5ac, H4K8ac, H4K12ac and H4K16ac decrease in mitotic cells[116]. Histone methylation, which has been also shown to affectgene expression [35], also changes during mitosis. Thus, H4K20meincreases in late G2/M [117] whereas both H3K27me and H3K36medecrease [116].

6. Other cell cycle-related processes

6.1. Cell fate

Both cell proliferation and fate specification are critical fornormal tissue development, to ensure that a proper number ofcells form the correct patterns in tissues and organs. This is whycoordination of cell proliferation with cell fate decisions is at thebasis of any developmental process. Mitosis involves nuclear reor-ganization, global chromosome condensation, and transcriptionsilencing and occurs concomitant with protein degradation and/ordisplacement of regulatory factors from chromosomes [118–121].One fundamental question is how cells specify their cell fate aftereach cell division when transcriptional competency is restored inprogeny cells [122]. These cells face the challenge to respond tohormonal, developmental, environmental and positional signals todecide their fate.

In Arabidopsis, the arrangement of hair and non-hair cell typeswithin the epidermis depends on the specification of trichoblasts,cells that do not express the homeobox gene GLABRA2 (GL2), whosechromatin remains accessible in atrichoblasts and becomes inac-cessible in trichoblasts [123]. The dynamics of cell fate specificationwithin the cell cycle is addressed elsewhere in this volume (Shawand Dolan). The GL2 pattern correlates with cell cycle-dependentchromatin changes within a small region of the GL2 promoter,which contains activating (H3ac and H3K9me3) marks in G1 andrepressive marks (H3K9me2) in G2/M [36]. It seems that the lateM/early G1 transition is a critical time for chromatin-dependentcell fate specification, determining the ‘on’/‘off’ state of GL2 andthe fate of the two newly formed cells by epigenetic modifications.It can be explained because the factors and/or the cellular staterequired for GL2 repression in trichoblasts are not available dur-ing the entire cell cycle and only during this M/G1 transition. Onepossibility is that these factors are targeted for proteolysis at themetaphase–anaphase transition. Other possibilities, such as pro-tein inactivation or reversion of the inhibitory histone marks, arealso plausible [124]. This mechanism explains how the chromatinstate is reset at mitosis and specified again during the following G1phase according to the underlying positional.

Alterations derived from the misfunction of CAF-1 also haveconsequences in cell fate decisions, i.e., altered root hair patternin fas2 mutants [123]. However, this does not appear to be thecase in haploid divisions during gametophyte development [125].The molecular basis of the phenotypes of fas1 and fas2 mutantsregarding cell fate are not known yet.

6.2. Chromatin-binding proteins

A large body of information is now available supporting the ideathat gene expression control is crucial for cell cycle progression andfor certain developmental transitions. The family of actin-relatedproteins (ARP) are revealing as key players in chromatin remodel-ing complexes relevant for the regulated activity of genes requiredfor plant growth [126]. Interestingly, Arabidopsis ARP4 and ARP7are nuclear proteins during interphase, although it is not knownwhether they remain associated to chromosomes [127]. Anotherexample of different subcellular localization of chromatin-bindingproteins is the major DNA methyltransferase MET1, crucial for themaintenance of the CpG methylation pattern, which is nuclear dur-ing interphase and is not bound to mitotic chromosomes [128].Thus, one can speculate that these chromatin-binding factors havea window at the end of mitosis before the nuclear envelope isformed to gain access to the chromatin in daughter nuclei. Thisis reminiscent of the cell cycle window which is also relevant forboth licensing of DNA replication origins and acquisition of cellfate [124]. Thus, the late M/early G1 and the S-phase appear as thetwo major cell cycle stages which are of particular relevance for anumber of cellular processes, including the change and/or mainte-nance of particular epigenetic landscapes in selected chromosomallocations [124,129].

6.3. Cell cycle exit and dedifferentiation

Repression of E2F target genes in mammalian cells upon perma-nent cell cycle exit is important for cell differentiation. H3K9me3increases in E2F target genes in differentiating cells but not incycling cells, a process which is dependent on the Suv39H histonemethyltransferase [130], indicating that the mechanism of E2F tar-get gene repression upon cell cycle exit is not the same as in cyclingcells. However, this may be different in Arabidopsis given the dif-ferent read-out of H3K9me3 in animal and plant cells. HDAC1 canalso interact with SUV39H1 suggesting that these two activities

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cooperate to mediate transcriptional repression [131,132]. In thiscontext, long-term silencing of selected genes in animal cells byPolycomb group (PcG) complexes appears to be mediated by Rb[133]. It is suggested that H3K27me3 plays a widespread role inrepressing irreversibly the expression of cell cycle genes during dif-ferentiation processes [133]. H3K27 methylation is mediated by thePcG repressive complex 2 (PRC2). Thus, PRC2 complexes introduceH3K27me3 marks at target genes, although the targeting mecha-nism is not known. Given the participation of Rb in this process ithas been speculated that E2F may help in the process of targetingPRC2 complexes to specific genes. These complexes, first discoveredin flies, are conserved in mammals and plants ([134,135]; see alsoGoodrich’s chapter in this volume). In plants, RBR interacts withmembers of PRC2 such as the homologue of Drosophila Extra sexcomb (ESC), FERTILIZATION INDEPENDENT ENDOSPERM (FIE) [136]and MSI1 protein [31,32], whereas binding of RBR to the SET domainhomolog of ENHANCER OF ZESTE (E(Z)), CURLY LEAF (CLF) has beenshown in yeast but not in plants [137]. The functional interactionof RBR and FIE and the ability of LHP1 to recognize H3K27me3 issuggestive of a possible pathway of repression of E2F targets byRBR through this histone mark, an aspect that should be addresseddirectly in the future.

In Arabidopsis, RBR interacts with FVE, a component of anHDAC complex, to repress FLOWERING LOCUS C (FLC) transcriptionthrough a histone deacetylation mechanism [138,139]. In addition,histone methylation can activate or repress transcription depend-ing on the number of methyl groups added and the residue targetedfor modification. Introduction of H3K4me3 correlates with tran-scriptional activation, a process that in human cells is mediatedby the MLL and SET histone methyltransferases, depending onthe H3ac level of target genes [140]. Interestingly, some E2F fac-tors interact with MLL, providing a mechanism for targeting H3K4methylation enzymes to specific genes. In mammalian cells, Rb canrecruit the histone methylase SUV39H1 at E2F target promotersto specifically methylate H3K9 residues. HETEROCHROMATIN PRO-TEIN 1 (HP1) recognizes this histone modification and binds to Rbto repress E2F activity at the cyclin E promoter [141]. Thus, thesemechanisms may account for the status of activating histone marksat E2F target genes in terminally differentiated cells as well as dur-ing the G1/S transition. However, the exact nature of such activatingmarks and their causal relationship with E2F-mediated transcrip-tional control is still far from being completely understood.

One peculiar aspect of plant cells is the ability of a variety of celltypes to dedifferentiate and return to a pluripotent state. The ded-ifferentiation process, which consists of two functionally distinctstages [142], is associated with redistribution of the HP1 proteinand with changes in the chromatin state of E2F target genes, e.g.RNR2 and PCNA, which remain as part of the condensed and silentchromatin in differentiated cells, decondensed but not active indedifferentiating cells and, finally, decondensed and active onlywhen cells return to the S-phase [143]. In this context, the differen-tiation process seems to require wide changes in the histone codeof differentiated cells. A screen for mutants defective in prolifera-tion and callus formation identified kyp-2 [144], a mutant in theKRYPTONITE (KYP) gene encoding a histone methyltransferase withreduced amount of H3K9me2 [145].

7. Concluding remarks

The available data clearly show that transcriptional regulationduring the cell cycle and some cell cycle transitions are associatedwith specific modifications at both the DNA and histone levels. Thecatalog of these modifications is increasing in size and is likely togrow more. However, we need to move from a static landscape to

a dynamic understanding of the role of epigenetic marks on cellcycle progression and cell cycle-dependent gene expression con-trol. Beyond the cellular level, cell division also plays a role at thelevel of the organism, and with a special emphasis during the post-embryonic organogenesis and development in plants. Therefore,understanding the impact of chromatin dynamics on plant growthand development should lead to major advances in the future.Thus, efforts should aim at identifying novel roles for specific chro-matin status as well as the complex protein interaction networksresponsible for interpreting chromatin changes into a biologicalprocess.

Acknowledgments

This work has been partially supported by grant BFU2006-5662(Ministry of Education and Science, Spain), and by an institutionalgrant from Fundación Ramon Areces.

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