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Available online at www.sciencedirect.com ScienceDirect 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 www.sciencedirect.com 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 www.sciencedirect.com 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 www.sciencedirect.com 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. www.sciencedirect.com 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], www.sciencedirect.com 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. References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1. Laux T: The stem cell concept in plants: a matter of debate. Cell 2003, 113:281-283. 2. Sinha N: Leaf development in angiosperms. Ann Rev Plant Physiol Plant Mol Biol 1999, 50:419-446. 3. Ikeuchi M, Sugimoto K, Iwase A: Plant callus: mechanisms of induction and repression. Plant Cell 2013, 25:3159-3173. 4. 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