Epigenetic memory transmission through mitosis and meiosis in plants

Seminars in Cell & Developmental Biology 19 (2008) 527–536

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Review

Epigenetic memory transmission through mitosis and meiosis in plants Hidetoshi Saze ∗ Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan

a r t i c l e

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Article history: Available online 31 July 2008 Keywords: Epigenetics DNA methylation Histone modification Arabidopsis Review

a b s t r a c t Gene activities can be regulated by epigenetic modifications of nucleotides and chromatin that are stably propagated through somatic cell divisions and, in some cases, across generations. The mechanisms that control epigenetic marks have recently been uncovered using model organisms, such as the flowering plant Arabidopsis thaliana. In Arabidopsis, perturbation of epigenetic gene activity often results in heritable developmental phenotypes. Stable, but potentially reversible, changes in epigenetic status can also be sources for phenotypic variations in natural plant populations. © 2008 Elsevier Ltd. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The molecular basis of epigenetic inheritance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. DNA methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Inheritance of DNA methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Histone modification and chromatin remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Inheritance of histone modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. RNA-directed DNA methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Inheritance of RNA molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigenetic inheritance of developmental phenotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Heritable developmental abnormalities induced in epigenetic mutants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Epigenetic changes induced by environmental stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Natural epigenetic variation in plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Genomic DNA is faithfully replicated and transmitted through mitosis leading to inheritance of identical genetic information by the two daughter cells. The differential expression of genes in various cell lineages during development, or prompt genetic responses to environmental stimuli, is achieved by the use of epigenetic mechanisms in cells to regulate gene activity. Epigenetic regulation of gene activities can be achieved by covalent modifications of nucleotides and chromatin. The modifications include

∗ Tel.: +81 55 981 6805; fax: +81 55 981 6804. E-mail address: [email protected]. 1084-9521/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcdb.2008.07.017

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DNA cytosine methylation and post-translational modifications of the core histone proteins, and are associated with production of small RNA molecules that can interact to form a self-reinforcing loop. The epigenetic modifications can mediate both a short-term (mitotic) and long-term (meiotic) transmission of an active or silent gene state without changing the primary DNA sequences. Specific enzymes are involved in the stable propagation of the epigenetic marks during DNA replication. Importantly, epigenetic marks are potentially reversible, which allows dynamic changes to be made in gene activity. Plants offer ideal model systems for the study of epigenetics as they have the wide range of epigenetic modifications that have been observed in other organisms. Indeed, studies in plants have revealed a number of enigmatic epigenetic phenomena. In addition,

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genome-wide profiles of epigenetic information (epigenome) are now available for the model plant Arabidopsis thaliana [1,2], which should further accelerate epigenetic researches in plants. In this review, I first describe the molecular basis for the inheritance of epigenetic modifications, based on recent discoveries in plants, animals and in vitro experimental systems. I mainly focus on the inheritance mechanisms for DNA methylation and histone modification. In later sections, I review the epigenetic inheritance of developmental phenotypes, principally in A. thaliana. The Arabidopsis studies have implications for heritable epigenetic variations observed in plant natural populations. 2. The molecular basis of epigenetic inheritance 2.1. DNA methylation In eukaryotes such as plants, fungi and mammals, cytosine residues in the genome are modified by methylation. DNA methylation occurs preferentially at repeat and transposon sequences, and DNA methylation particularly in 5 control regions is generally associated with transcriptional repression and/or silencing of genes [3–5]. DNA methylation is also important for regulation of developmental genes [6]. In plants, DNA methylation is mediated by DNA methyltransferases that target cytosines in all contexts (CG, CHG and asymmetric CHH; where H represents A, T, or C) [7,8]. Plant DNA methyltransferases show a preference for a subset of target sequences. In Arabidopsis, methylation at CG sites is maintained by METHYLTRANSFERASE1 (MET1), and non-CG methylation is redundantly maintained by DOMAINS REARRANGED METHYLTRANSFERASE1/2 (DRM1/2) and CHROMOMETHYLASE3 (CMT3) [8–10]. In addition to the DNA methylases, the chromatin remodeling factor Decrease in DNA Methylation1 (DDM1) is required to maintain both CG and non-CG methylation at repetitive sequences [10,11]. Chromatin components and RNA interference (RNAi) factors are involved in de novo DNA methylation at cytosines in all contexts, a phenomenon known as RNA-directed DNA methylation (RdDM) [12,13]. Genome-wide analyses of DNA methylation and small RNAs in Arabidopsis using tilling array technology provided the first profiles of an epigenome of a higher eukaryote [14,15]. As expected from an earlier report [16], the Arabidopsis genome has dense DNA methylation in heterochromatic regions in which many transposable elements and repetitive sequences reside. The studies also showed that approximately ∼30% of actively transcribed gene sequences were DNA methylated. Further studies of the Arabidopsis epigenome at a single-base resolution level using a bisulfite-sequencing method showed that genic methylation occurs mainly at CG sites in the coding region of the genes [17,18]. However, the function of this methylation is not yet clear. 2.2. Inheritance of DNA methylation Immediately after S-phase, the newly synthesized DNA strands are unmethylated. In 1975, Holliday & Pugh and Riggs independently predicted the presence of methyltransferases that carry out maintenance methylation during DNA replication. These DNA methyltransferases were predicted to have a substrate preference for the hemi-methylated DNA strand and would establish the DNA methylation pattern on the unmethylated strand [19,20]. The semi-conservative replication of DNA methylation by maintenance methylases enables the faithful propagation of pre-existing DNA methylation patterns from a mother cell to daughter cells through successive rounds of DNA replication. In mammals, DNA methylation occurs exclusively at symmetric CG sites, and is maintained by DNA methyltransferase 1 (Dnmt1) [7]. Dnmt1 shows a preference in vitro for methylation of

hemi-methylated DNA strand substrates, and associates with Proliferating Cell Nuclear Antigen (PCNA) at DNA replication foci [21–24]. This behavior indicates that Dnmt1 is required for the replicationcoupled maintenance of DNA methylation during S-phase of the cell cycle. In plants, the Dnmt1 homolog, MET1 is believed to be responsible for maintenance of DNA methylation at CG sites. The loss of MET1 activity, either induced by an antisense MET1 transgene or through mutations of the MET1 gene, results in reduction of CG methylation [25–28]. Although there are no unequivocal biochemical data that demonstrate the MET1 class enzymes of plants have a maintenance DNA methylation activity, the genetic evidence supports the view that MET1 is orthologous to Dnmt1 (Fig. 1A). MET1 activity is required for maintenance of CG methylation throughout plant the life cycle [28–30]. Loss of CG methylation by mutation of MET1 or DDM1 cannot be reversed even in the presence of the wild-type proteins, and the hypomethylation state is transmitted for multiple generations [27,28,31]. In addition to methylation at symmetric CG sites, plant genomes also show DNA methylation at partially symmetric CHG and asymmetric CHH sites. The non-CG sites are methylated by CMT3 and DRM1/DRM2 in Arabidopsis [9,32]. Plants with the cmt3 mutation show loss of most of the CHG methylation in the genome [18], suggesting that CHG sites are the primary target of CMT3. Interestingly, similarly to CG methylation, CHG methylation on one strand is highly correlated with CHG methylation on the opposing strand [18]. Furthermore, asymmetric methylation at CHHG sites also shows a tendency for symmetrical methylation on the opposite strand [18]. Whether CMT3 can recognize hemi-methylation and is capable of maintenance methylation at such partially symmetric sites during DNA replication remains to be determined. CHG methylation is mediated by the chromodomain of CMT3, which binds directly to histone H3 lysine 9 methylation (H3K9me) and lysine 27 methylation (H3K27me) [33]. This suggests that CHG methylation does not necessarily occur in a DNA replication-coupled manner that depends on the pre-existing CHG methylation pattern. Rather, propagation of CHG methylation patterns through DNA replication might be achieved by pre-existing histone modification. Maintenance of asymmetric cytosine methylation in a semiconservative manner is theoretically impossible since a newly synthesized DNA strand has a guanine at the complementary position of asymmetric cytosine sites, and therefore the second round of DNA replication results in the loss of the initial methylation at the corresponding cytosine. This implies that cytosine methylation at asymmetric sites must be maintained by continuous de novo methylation activities, and that the methylation depends on other surrounding epigenetic marks such as CG/CHG methylation, histone modification, small RNAs, or perhaps the primary DNA structure itself. In Arabidopsis, DRM1/DRM2 form part of the RdDM pathway and are responsible for de novo DNA methylation in all cytosine contexts. In contrast to CG methylation, non-CG methylation seems to be rapidly re-established by these other epigenetic modifications, since developmental abnormalities induced in cmt3/drm1/drm2 triple mutants are rapidly restored by reintroduction of CMT3 and/or DRM2 activities [32]. Recent studies in plants and mammals showed that the semiconservative replication of DNA methylation patterns in the S-phase of the cell cycle requires proteins containing an SRA domain (SET and RING finger-associated domain). A screen of Arabidopsis natural accessions for changes in the DNA methylation patterns of centromeric repeats identified the gene VARIANT IN METHYLATION1 (VIM1) [34]. Plants with a mutation of VIM1 showed CG and CHG hypomethylation and decondensation of centromeres. The SRA domain of VIM1 can bind to methylated CG and CHG oligonucleotides in vitro. The mammalian homolog of VIM1, Np95/UHRF1, co-localizes with PCNA and DNMT1 during S-phase, and medi-

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Fig. 1. Putative models of inheritance of epigenetic modifications during DNA replication. Filled lollipops represent DNA methylation, and stars represent histone modifications. (A) A semi-conservative replication model of DNA methylation pattern during S-phase. MET1 might bind to PCNA and putative SRA domain proteins as suggested in mammalian systems (see the main text). MET1 adds methyl groups on the hemi-methylated DNA templates. DNA methylation stimulates recruitment of histone methyltransferases (HMTs) that have an SRA domain. (B) A conservative nucleosome replication model. In this model, parental histone octamers (blue) segregate randomly to both daughter DNA strands, and newly synthesized histone octamers (yellow) fill the gaps. Histone modifications on parental nucleosomes might propagate similar modifications to adjacent nucleosomes. (C) A semi-conservative nucleosome replication model. Parental histone octamers might be split into two, and epigenetic modifications of each half of the parental nucleosome might be copied onto the newly incorporated histone proteins. met1: METHYLTRANSFERASE1. SRA domain: SET and RING finger-associated domain. PCNA: Proliferating Cell Nuclear Antigen.

ates the loading of DNMT1 to replicating heterochromatic regions [35,36]. Np95/UHRF1-deficient cells show both global and local loss of DNA methylation, and the SRA domain of Np95/UHRF1 preferentially associates with the hemi-methylated DNA strand, showing that the SRA protein is required for DNMT1-mediated maintenance

of DNA methylation during S-phase. Intriguingly, Arabidopsis VIM1 specifically acts at centromeric repeats and the vim1 mutation has no significant effects on DNA methylation at 5 s rRNA pericentromeric repeats [34]. In addition, hypomethylation of CG and CHG in vim1 plant is restored rapidly in F1 hybrids of vim1 plants crossed

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with wild-type plants. This restoration is in sharp contrast with the inheritance of CG hypomethylation in ddm1 or met1 plants. It is not clear whether MET1 and other methylases can be recruited by VIM1 to replication foci during S-phase in Arabidopsis (Fig. 1A). In addition to the SRA domain, VIM1 and Np95/UHRF1 have one or two RING (Really Interesting New Gene) finger domains. The RING finger domain of Np95/UHRF1 has histone mono-ubiquitin ligase activity [37]. It is not clear whether VIM1 also has histone ubiquitin ligase activity, and if so, how histone ubiquitylation affects the maintenance of DNA methylation. In mammals, genome-wide reprogramming of epigenetic modifications occurs in female and male gametogenesis, and in early embryogenesis [38,39]. The reprogramming process includes active DNA demethylation and passive DNA demethylation followed by re-establishment of the DNA methylation pattern, although the enzymes responsible for the active demethylation have not yet been identified. In contrast, it has been shown that plants have DNA glycosylase/lyases that are involved in DNA demethylation. These enzymes can excise a 5-methylcytosine base and introduce a nick into the DNA backbone, and thereby enable the DNA repair pathway to insert an unmethylated cytosine nucleotide. To date, however, there is no direct evidence that these proteins are involved in the genome-wide reprogramming of DNA methylation in plants. One argument against the likelihood of genome-wide reprogramming of DNA methylation in plants is the fact that of the re-imposition of DNA methylation is extremely slow, and hypomethylation states can be stably inherited through several round of meiosis [31,40,41]. Nevertheless, immunohistochemical studies using an anti-5-methylcytosine antibody detected a genome-wide reduction of DNA methylation in some plant species during gametogenesis or early embryogenesis. Oakeley et al. reported that during the development of pollen in tobacco, immunostaining of the generative nucleus, the pollen nucleus that develops to form the sperm nuclei, indicated a dramatically decreased level of DNA methylation compared with the vegetative nucleus [42]. A rapid decrease in global DNA methylation, independent of DNA replication, was also observed during seed germination in Silene latifolia [43]. Further experiments are needed to clarify whether these observations indeed reflect the presence of genomewide reprogramming of DNA methylation in these plant species and to determine whether this is a general phenomenon across the plant kingdom. The plant life cycle includes haploid gametophytic phases where several rounds of cell division occur. During post-meiotic cell division, MET1 is required for the inheritance of the CG methylation pattern. Depletion of MET1 activity in female and male gametogenesis causes loss of DNA methylation of chromosomes, resulting in variation of local DNA methylation patterns between met1 gametes likely due to random chromosome segregation during the postmeiotic cell divisions [28]. The methylation pattern of each gamete is then propagated through successive rounds of DNA replication and transmitted to heterozygous met1 progenies. However, except met1 mutant alleles, the gametophytic effect of the mutant alleles of genes affecting DNA methylation in Arabidopsis, including cmt3, drm1/drm2 and ddm1, has not been reported [28,31,44–46]. A dominant mutation of the maize homolog of CMT3 (ZMET2) has been described [47]. However, the mutant also expressed dominance during somatic development and, therefore, it is not clear whether its effect is due to loss of DNA methylation during post-meiotic DNA replication as seen in met1. These data indirectly suggest a minor role for these epigenetic modifiers in the propagation of DNA methylation during plant gametogenesis. In addition, it appears that DNA hypomethylation in met1 gametes in the post-meiotic cell divisions cannot be rescued by the presence of wild-type MET1 protein as well as other methyltransferases and histone

modifiers. In mammals, CG methylation is targeted by methyl-CG binding domain (MBD) proteins that can recruit histone modifiers such as histone deacetylases (HDACs), the H3K9 methyltransferases SUV39H1 and SETDB1, and heterochromatin protein1 (HP1) to form repressive chromatin states [48–51]. Dnmt1 also directly interacts with HDACs, SUV39H1, and another H3K9 methyltransferase G9a [52–54]. Thus, CG methylation and/or Dnmt1 itself can provide a platform for other epigenetic modifications. In Arabidopsis, the met1 mutation causes a significant reduction of non-DNA methylation and H3K9 methylation at heterochromatic loci [17,18,55–57]. H3K9 methylation in Arabidopsis is maintained by SET domain proteins including KRYPTONITE/SUVH4 (KYP/SUVH4) SUVH5, SUVH6 and AtSUVH2 [58–61]. Since KYP/SUVH4 contains an SRA domain that can bind to double-stranded oligonucleotides containing 5methylcytosine in all contexts in vitro [62], CG methylation by MET1 likely recruits the histone methylases that add the repressive H3K9 methylation marks at heterochromatic loci (Fig. 1A). H3K9 methylation can further recruits CMT3 [33], suggesting a self-reinforcing loop of DNA methylation and H3K9 methylation. 2.3. Histone modification and chromatin remodeling In addition to DNA methylation, covalent modifications of histone proteins are essential for epigenetic regulation of gene activity. Histone modifications regulate a number of cellular events such as expression or silencing of genes, DNA repair and chromatin condensation. Chromatin consists of a beads-like structure of nucleosome arrays. Each nucleosome is an octamer of two each of H2A, H2B, H3 and H4 proteins (core histone octamer) around which is coiled a 146 base pair (bp) of DNA strand. The N-terminal and C-terminal tails of histone proteins are subject to various combinations of modifications that include methylation, acetylation, phosphorylation and ubiquitylation (reviewed in [63]). Although DNA methylation is generally associated with a repressive chromatin state, histone modifications are associated with activation and silencing of gene expression. Importantly, histone modifications can be reversed by specific enzymes such as HDAC and histone demethylases, enabling dynamic changes in chromatin states [64,65]. In addition to the covalent modification of histone proteins, dynamic structural changes in chromatin are involved in the epigenetic regulation of genes. In Arabidopsis, CG and non-CG methylation and H3K9 methylation at heterochromatic loci are maintained by DDM1 [11,16,66]. DDM1 is able to promote chromatin remodeling such as sliding of mononucleosomes on DNA templates in an ATP-dependent manner in vitro [67]. The DDM1 homolog in mammals, lymphoid-specific helicase (Lsh) in mammals is also required for maintenance of DNA methylation [68], suggesting a conserved mechanism of chromatin remodeling for maintenance of DNA methylation. Although it is still not clear how the chromatin remodeling activity of DDM1 affects DNA and histone methylation in vivo, DDM1 might influence the accessibility of chromatin to DNA methyltransferases by altering nucleosome structures [69]. 2.4. Inheritance of histone modifications In contrast to the mechanism of replication and inheritance of DNA methylation patterns during DNA replication, the mechanism of transmission of histone modifications through mitosis and meiosis is not well understood. As discussed above, the stable propagation of DNA methylation can direct subsequent H3K9 methylation that leads to the formation of a repressive chromatin state. However, in some organisms such as Neurospora crassa, DNA methylation appears to be controlled solely by H3K9 methylation, because depletion of the H3K9 methylase, Dim-5, completely abol-

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ishes DNA methylation in the genome [70]. In addition, epigenetic inheritance of abnormal phenotypes across multiple generations has been reported in the model organisms Drosophila melanogaster and Caenorhabditis elegans [71,72] whose genomes have little or no DNA methylation [73,74]. These phenotypes were suppressed by treatment with the HDAC inhibitor trichostatin A or by depletion of chromatin remodeling proteins [71,72], implying that long-term transmission of the abnormal phenotypes may be mediated by histone-based inheritance of epigenetic information. During DNA replication, newly synthesized histone octamers need to be deposited onto the two daughter DNA strands for de novo nucleosome assembly [75,76]. In replication-coupled nucleosome assembly, H3 and H4 are first deposited onto new DNA strands, followed by H2A and H2B deposition. Early biochemical studies and direct electron microscopic observations of chromatin replication have provided evidence for the segregation of parental histone proteins to newly replicated DNA; this observation stimulated the development of the “conservative” nucleosome replication model (Fig. 1B) [77]. In this model, histone octamers segregate randomly to both daughter DNA strands during S-phase, and newly synthesized histone octamers fill the gaps. Therefore, in this model, epigenetic modifications of parental nucleosomes would be diluted by successive rounds of replication. In order to transmit epigenetic states through DNA replication, histone modifications on inherited nucleosomes need to propagate similar modifications on adjacent newly synthesized nucleosomes. Alternatively, inheritance of histone modifications during DNA replication could also be explained by a “semi-conservative” nucleosome replication model (Fig. 1C) [75,77]. In semi-conservative nucleosome replication, an (H3/H4)2 tetramer could be split into two H3/H4 dimers, and the dimer would then be used for reassembly of a new nucleosome with a newly synthesized H3/H4 dimer. This would allow stable transmission and propagation of histone modifications through DNA replication by ensuring that epigenetic modification on the half parental nucleosome could be copied to the other half carrying the newly incorporated histone proteins. Although the currently available experimental data supporting this model are poor, recent biochemical and structural studies have shown that the major histone H3 (H3.1) and the histone variant H3.3 exist as H3.1/H4 or H3.3/H4 dimeric units in nucleosome assembly complexes, and also that a histone chaperone CIA/ASF1 has the ability to split an (H3–H4)2 tetramer [78,79]. These data lend support to the possibility of semi-conservative assembly of histone octermers during DNA replication. In contrast to the DNA replication-coupled deposition of histone H3, the histone variant H3.3 can be deposited onto actively transcribed loci in a replication-independent manner throughout the cell cycle, by replacing H3 [80,81]. Recently, it was shown that the persistence of an active gene state over several cell divisions could be mediated by H3.3 [82]. Ng and Gurdon observed in nuclear transfer experiments using Xenopus laevis that an “epigenetic memory” of an active gene state persists regardless of new cell lineages, even after two rounds of nuclear transfer that represent more than 24 mitotic cell divisions. Epigenetic memory was not affected by treatment with the DNA methylation inhibitor 5-azaC, but was abolished by a mutation at K4 of H3.3. Moreover, over-expression of wildtype H3.3 increased the efficiency of memory transmission. This result provides direct evidence that an active chromatin state can be transmitted through successive cell divisions by a histone-based mechanism. 2.5. RNA-directed DNA methylation RNA interference machinery and small RNA molecules direct DNA methylation and histone modifications, and mediate hete-

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rochromatin formation and transposon silencing in yeast, animals and plants [12,83,84]. In fission yeast, siRNA produced from pericentromeric repeats is loaded onto the RNA-induced Initiation of Transcriptional gene Silencing (RITS) complex that subsequently recruits the H3K9 methylase Clr4 [84]. In plants, however, siRNAdirected control of histone modification by a RITS-like complex has not been reported. In contrast, the RNA-based RdDM appears to control establishment of DNA methylation. RdDM is responsible for transgene-induced de novo DNA methylation as well as non-CG methylation at endogenous repeat loci [12]. In Arabidopsis, this process requires a subset of RNAi components such as ARGONAUTE4 (AGO4) AGO6, DICER-LIKE3 (DCL3) and RNA-DEPENDENT RNA POLYMERASE2 (RDR2), which generate small RNAs in the size of 24–26 nucleotides (small interfering RNA; siRNA) from aberrant RNA or double-stranded RNA (dsRNA) precursors. In addition to the RNAi machinery, an SNF2-like chromatin remodeling protein DRD1, and an SMC-like protein DMS3 [85] play roles in dsRNA-induced de novo methylation at non-CG contexts. Additionally, subunits of the plant specific RNA polymerase IV are required for siRNA production and the direction of DNA methylation to the corresponding DNA templates. It is not known, however, whether the PolIV complex uses DNA or RNA as templates to generate siRNA. 2.6. Inheritance of RNA molecules RNA molecules may have the potential to mediate longterm transmission of epigenetic information. An RNA-mediated inheritance of epigenetic information has been observed in a paramutation-like phenomenon in kit mutant mice [86]. Null mutants of Kit gene are lethal, while heterozygous mice exhibit a white tail tip and feet phenotypes; the phenotypes are also exhibited by the wild-type progeny of heterozygous mice. Interestingly, microinjection of total RNA isolated from heterozygous mice into wild-type fertilized eggs induced a heritable white tail phenotype, suggesting that the RNA molecules transmitted the epigenetic information that determined the phenotype. In plants, RNA molecules are able to move through plasmodesmata and phloem, and can spread throughout the plant [87]. The RNA signals mediate a systemic spreading of RNA silencing, which has often been observed in transgenic and virus-infected plants. However, the transmission of such RNA signals through meiosis has not well been thoroughly investigated. Interestingly, large endogenous dsRNA replicons have been identified in many plant species including rice and barley [88]. The dsRNAs (about 14 kb in rice), named endornaviruses, can replicate independently of their host genome without inducing disease symptoms in the host. Endornaviruses can be transmitted very efficiently from the host to its progeny plants through both eggs and pollen [89], suggesting a possible RNA inheritance mechanism in plants. 3. Epigenetic inheritance of developmental phenotypes Heritable epigenetic changes in gene activity often affect plant development. Developmental abnormalities are frequently found in laboratory mutant strains with disturbed epigenetic modifications. Inheritance of epigenetic traits has also been observed in naturally propagating plant populations. Some epigenetic traits are extremely stable and show typical Mendelian inheritance; they are, therefore, sometimes indistinguishable from genetic mutations. Other epigenetic traits show non-Mendelian inheritance, or variable expressivities and reversion to the wild-type phenotype due to the meta-stable nature of epigenetic alleles [90,91]. Non-Mendelian inheritance of epigenetic traits is well documented in paramutations in maize (reviewed in [92]). At the b1

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locus in maize, the paramutagenic B allele changes the paramutable B-I allele to B in B /B-I heterozygous F1 plants; this change results in a loss of purple color pigmentation. The newly paramutated B * allele then becomes paramutagenic, and this epigenetic state can be stably inherited by subsequent generations. Paramutation in the b1 locus requires tandem repeats of an 853 bp sequence located 100 kb upstream of the b1 gene. A genetic screen for modifier of paramutation (mop) identified an RNA-dependent RNA polymerase MOP1 that is similar to Arabidopsis RDR2 [93], suggesting an RNA-mediated mechanism plays a role in paramutation. In addition, an SNF2-like chromatin remodeling protein RMR1 has been shown to be required for paramutation at the pl1 locus [94]. 3.1. Heritable developmental abnormalities induced in epigenetic mutants The impact of epigenetic changes on genome integrity and plant development has been examined directly using mutants of epigenetic modifiers. ddm1 and met1 mutations in Arabidopsis cause global DNA hypomethylation and reactivation of normally silent transposon sequences [55,95–100], indicating that the primary target of epigenetic modifications is the endogenous repetitive elements. Inbred ddm1 and met1 lines exhibit various developmental abnormalities, some of which are heritable even in the presence of the wild-type alleles [27,31,41]. Analysis of the heritable abnormalities has revealed that the most of the affected loci are associated with changes in epigenetic modification of repetitive elements. One of the abnormalities induced by ddm1 is clam, in which a DNA-type transposon CACTA was reactivated, and caused an insertional mutation [97]. ddm1 or met1 mutation also induces heritable epigenetic mutations in other genomic loci without changing DNA sequences, which thus mimicking genetic mutations. Another ddm1-induced abnormality is bal, which shows constitutive pathogen responses and a dwarfed phenotype, and the candidate locus is associated with an R-gene cluster and retrotransposon [101,102]. A gain-of-function epigenetic mutation fwa in Arabidopsis has well been characterized [40,103–106] (Fig. 2A). In wild-type somatic tissues, FWA is transcriptionally silenced due to DNA methylation of SINE-related tandem repeats at the promoter region. ddm1 or met1 mutation causes erasure of the DNA methylation at the repeats, leading to ectopic expression of FWA transcripts and induction of a dominant late-flowering phenotype in the fwa plant [27,40,41,106]. The hypomethylation state of the repeats and the active transcription of FWA is extremely stable even in the presence of wild-type DDM1 and MET1 alleles, and can be inherited for multiple generations [40]. Since the FWA protein directly binds to the FT protein in vitro, the dominant late-flowering phenotype in the fwa plant is likely due to the inhibition of FT function by the over-production of FWA proteins [107]. Interestingly, FWA is an imprinted gene that is specifically expressed in the endosperm specifically from the maternally inherited alleles (Fig. 2A). The reactivation of FWA in the endosperm involves active DNA demethylation of the tandem repeats, which depends on DME activity [104]. Re-introduction of the SINE-related repeats into the Arabidopsis genome by Agrobacterium transformation efficiently elicits de novo methylation of the transgene and the endogenous homologous sequence, a process that requires de novo methylase DRM and RNAi factors [103,108]. However, it is not clear how the unmethylated state of the FWA promoter in fwa is stably inherited, even in the presence of the siRNA of the corresponding sequence [103]. Paradoxically, global DNA hypomethylation in ddm1 or met1 plants induces ectopic local DNA hypermethylation at some genomic loci. Antisense MET1 transgenes or the ddm1 mutation cause local DNA hypermethylation and silencing of SUPERMAN

(SUP) (Fig. 2B) [109,110]. The hypermethylation of SUP occurs at pyrimidine-rich sequences containing CT dinucleotide repeats in the promoter. Loss-of-function of SUP results in homeotic changes in flower structure, in particular, an increase in the number of stamens. Epigenetic alleles of SUP, named clark kent (clk) alleles, revert to the normal allele at about 3% per generation [110]. A screen for mutants impaired in the sup silencing recovered mutations in CMT3, KYP/SUVH4 and AGO4, suggesting that the hypermethylation and silencing are mediated by H3K9 methylation and non-CG methylation [45,59,111,112]. Depletion of MET1 also causes DNA hypermethylation at AGAMOUS (AG) [109]. Similar to the SUP, hypermethylation occurs at CT-rich repeats in the promoter and second intron of AG. Another ddm1-induced heritable abnormal phenotype is bonsai (bns), first identified in a propagating population of ddm1 plants [41]. bns plants exhibit a reduction of plant height and aberrant phyllotaxis. The phenotype is stably inherited on a ddm1 background, and persists in the presence of wild-type DDM1 although the phenotype becomes unstable. Using a map-based approach and transcription analysis, bns was shown to be a loss-of-function type epigenetic mutation that is associated with DNA hypermethylation and silencing of BNS [113] (Fig. 2C). BNS gene encodes a 63 aa peptide, similar to a subunit of Anaphase-Promoting Complex. Interestingly, BNS is flanked by a non-LTR type retrotransposon (LINE) sequence in a tail-to-tail orientation (Fig. 2C). Repeated selfpollination of ddm1 plants induced hypermethylation of the BNS gene, while the flanking LINE sequence showed hypomethylation. This is consistent with the primary role of DDM1 in the maintenance of DNA methylation at transposon sequences. The flanking LINE sequence is polymorphic in Arabidopsis natural accessions; an Arabidopsis natural accession Cvi that lacks the LINE insertion at the BNS locus did not show the induction of methylation on a ddm1 background, suggesting that the hypermethylation is mediated by the flanking LINE sequence. Since BNS hypermethylation in ddm1 occurs by spreading from the LINE into the BNS region, the pre-existing epigenetic modifications on the LINE and/or the properties of the LINE sequence itself may be required for ddm1induced BNS hypermethylation. Several observations suggest that the hypermethylation at BNS in ddm1 seems to be mediated by distinct mechanisms from that of SUP and AG. In the case of the bns epi-allele, methylation is found primarily in the middle and the downstream segments of the gene, while the promoter region is free from methylation [113]. In addition, the SUP and AG loci appear to lack transposable elements in the vicinity of their locations. Although the precise mechanism of BNS hypermethylation in ddm1 plants is still unclear, RNA-directed and histone-mediated methylation models have been proposed [113]. Recently it was shown that global hypomethylation caused by the met1 mutation triggers inhibition of the DNA demethylation pathway and activation of the de novo methylation and H3K9 methylation pathways [114]. Notably, high-resolution mapping of DNA methylation in the met1 plant genome showed that erasure of gene-body methylation of CG sites triggers hypermethylation at CHG sites within genes [17,18]. This local hypermethylation at a number of loci may compensate for the global loss of DNA methylation. 3.2. Epigenetic changes induced by environmental stimuli Various environmental stimuli potentially influence the epigenetic state of genes. Reactivation of transposable elements in response to stress was first suggested by McClintock [115], and now it is known that both biotic and abiotic stresses activate transposons in plants [116–119]. Epigenetic changes induced by various stresses can be transmitted through meiosis. Arabidopsis plants treated with

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Fig. 2. Heritable epi-allele formation in Arabidopsis hypomethylation mutants. Boxes colored light blue represent genes. Repeat-related sequences are colored pink. Transcripts are indicated by arrows with dashed lines. Filled lollipops represent DNA methylation. (A) fwa epi-allele. FWA is an imprinted gene that is expressed from the maternal allele in wild-type endosperm. (B) clark kent allele of SUP. (C) bonsai epi-allele. met1: METHYLTRANSFERASE1. ddm1: DECREASE IN DNA METHYLATION1. SUP: SUPERMAN. LINE: a non-LTR type retrotransposon.

UV-C or a pathogenic flagellin peptide show increased levels of homologous recombination [120,121]. Interestingly, the phenotype with the elevated level of homologous recombination persisted for at least four generations in untreated progeny, indicating that an epigenetic memory of the stress treatment becomes meiotically heritable [122]. The epigenetic memory acts as a dominant trait, and can be transmitted maternally and paternally to successive generations. However, the underlying mechanism of the epigenetic memory transmission, and the mediator of the epigenetic memory are still unknown. 3.3. Natural epigenetic variation in plants Epigenetic mutations in developmental genes often occur spontaneously in naturally propagating plant populations. For instance, a naturally occurring floral symmetry change in Linaria vulgaris is caused by an epigenetic mutation of the Linaria cycloidea (Lcyc) gene [123]. In the “peloric” mutant, the Lcyc gene is hypermethylated and transcriptionally silenced. The mutant phenotype is heritable but occasionally reverts to wild type during somatic development; this reversion is correlated with a reduction in the methylation of Lcyc. Another example of a naturally occurring epigenetic mutation is Colorless non-ripening (Cnr) in tomato [124]. The Cnr phenotype is due to silencing of an SBP-box gene as a result of DNA hypermethylation of the promoter region. The Cnr epigenetic mutation is

very stable; revertant ripening sectors were observed in only three fruits from more than 3000 independent plants. Although only a few examples of naturally occurring epigenetic phenotypes have been reported, many more “hidden” epigenetic variations that are less apparent than that of Lcyc and Cnr must be present in plant populations. Natural accessions of A. thaliana can be an ideal model to investigate genetic and epigenetic variations in a plant population [125,126]. A screen for genomic sequences showing epigenetic variation among natural strains of Arabidopsis identified a nonautonomous non-LTR retrotransposon family named Sadhu [127]. The Sadhu family shows variation in DNA methylation at sequences associated with transcript level polymorphisms between Arabidopsis strains. The epigenetic states of Sadhu elements are stable and meiotically heritable. Interestingly, members of the Sadhu family showed different responses to mutations of ddm1, met1 and a histone deacetylase hda6, suggesting locus specific epigenetic regulation of the elements [128]. Epigenetic control of Phosphoribosylanthranilate isomerase2 (PAI2) is another example of differential epigenetic regulation of endogenous sequences in Arabidopsis strains [129]. PAI2 is unmethylated in the majority of Arabidopsis strains, but strains with an inverted repeat of PAI1PAI4, highly similar to PAI2, have high methylation and silencing of PAI2. The PAI1-PAI4 repeat can trigger de novo methylation of an unmethylated PAI2 locus in trans. Genetic studies showed that the

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methylation of PAI2 requires CMT3 and KYP/SUVH4, and that the trigger of methylation involves RNA signals [129]. A recent study reported epigenetic variation in FWA gene regulation in the genus Arabidopsis [105]. The SINE-related sequence in the promoter of FWA is highly diverse between Arabidopsis species and, although the promoters are methylated, FWA expression is imprinted even in species without the tandem repeat structure seen in A. thaliana. FWA shows intra-specific variations in expression in vegetative tissues. Since FWA gene potentially influences flowering time, the variable epigenetic regulation of FWA might contribute to generate natural variation in reproductive timing. 4. Conclusion Epigenetic modifications can be maintained stably for many cell generations. This stability contributes to the transmission of epigenetic traits for multiple generations. In contrast to genetic alterations, however, epigenetic modifications are potentially reversible. Our understanding of the dynamic regulation of epigenetic modifications and chromatin structures during plant development will be enhanced by a greater knowledge of DNA demethylation and histone demethylation pathways in plants [130–134]. Such pathways might be involved in cell or tissue type specific epigenetic regulation of gene activity. As a consequence of their sessile nature, plants are continuously challenged by environmental stresses. Environmental cues might activate as yet unidentified pathways that elicit epigenetic changes both in genes and transposable elements, generating heritable epigenetic variations in natural populations. Acknowledgement I would like to thank T. Kakutani for critical reading of the manuscript. References [1] Zhang X. The epigenetic landscape of plants. Science 2008;320:489–92. [2] Zhu JK. Epigenome sequencing comes of age. Cell 2008;133:395–7. [3] Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006;31:89–97. [4] Yoder JA, Walsh CP, Bestor TH. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 1997;13:335–40. [5] Martienssen RA, Colot V. DNA methylation and epigenetic inheritance in plants and filamentous fungi. Science 2001;293:1070–4. [6] Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002;16:6–21. [7] Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005;74:481–514. [8] Henderson IR, Jacobsen SE. Epigenetic inheritance in plants. Nature 2007;447:418–24. [9] Chan SW, Henderson IR, Jacobsen SE. Gardening the genome: DNA methylation in Arabidopsis thaliana. Nat Rev Genet 2005;6:351–60. [10] Kakutani T, Kato M, Kinoshita T, Miura A. Control of development and transposon movement by DNA methylation in Arabidopsis thaliana. Cold Spring Harb Symp Quant Biol 2004;69:139–43. [11] Vongs A, Kakutani T, Martienssen RA, Richards EJ. Arabidopsis thaliana DNA methylation mutants. Science 1993;260:1926–8. [12] Matzke M, Kanno T, Huettel B, Daxinger L, Matzke AJ. Targets of RNA-directed DNA methylation. Curr Opin Plant Biol 2007;10:512–9. [13] Matzke MA, Birchler JA. RNAi-mediated pathways in the nucleus. Nat Rev Genet 2005;6:24–35. [14] Zhang X, Yazaki J, Sundaresan A, Cokus S, Chan SW, Chen H, et al. Genomewide high-resolution mapping and functional analysis of DNA methylation in arabidopsis. Cell 2006;126:1189–201. [15] Zilberman D, Gehring M, Tran RK, Ballinger T, Henikoff S. Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription. Nat Genet 2007;39:61–9. [16] Lippman Z, Gendrel AV, Black M, Vaughn MW, Dedhia N, McCombie WR, et al. Role of transposable elements in heterochromatin and epigenetic control. Nature 2004;430:471–6.

[17] Lister R, O’Malley RC, Tonti-Filippini J, Gregory BD, Berry CC, Millar AH, et al. Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 2008;133:523–36. [18] Cokus SJ, Feng S, Zhang X, Chen Z, Merriman B, Haudenschild CD, et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature 2008;452:215–9. [19] Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development. Science 1975;187:226–32. [20] Riggs AD. X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet 1975;14:9–25. [21] Leonhardt H, Page AW, Weier HU, Bestor TH. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 1992;71:865–73. [22] Bestor TH. Activation of mammalian DNA methyltransferase by cleavage of a Zn binding regulatory domain. EMBO J 1992;11:2611–7. [23] Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF. Human DNA-(cytosine5) methyltransferase-PCNA complex as a target for p21WAF1. Science 1997;277:1996–2000. [24] Iida T, Suetake I, Tajima S, Morioka H, Ohta S, Obuse C, et al. PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA. Genes Cells 2002;7:997–1007. [25] Ronemus MJ, Galbiati M, Ticknor C, Chen J, Dellaporta SL. Demethylationinduced developmental pleiotropy in Arabidopsis. Science 1996;273: 654–7. [26] Finnegan EJ, Peacock WJ, Dennis ES. Reduced DNA methylation in Arabidopsis thaliana results in abnormal plant development. Proc Natl Acad Sci USA 1996;93:8449–54. [27] Kankel MW, Ramsey DE, Stokes TL, Flowers SK, Haag JR, Jeddeloh JA, et al. Arabidopsis MET1 cytosine methyltransferase mutants. Genetics 2003;163:1109–22. [28] Saze H, Mittelsten Scheid O, Paszkowski J. Maintenance of CpG methylation is essential for epigenetic inheritance during plant gametogenesis. Nat Genet 2003;34:65–9. [29] Takeda S, Paszkowski J. DNA methylation and epigenetic inheritance during plant gametogenesis. Chromosoma 2005:1–9. [30] Jullien PE, Kinoshita T, Ohad N, Berger F. Maintenance of DNA methylation during the Arabidopsis life cycle is essential for parental imprinting. Plant Cell 2006;18:1360–72. [31] Kakutani T, Munakata K, Richards EJ, Hirochika H. Meiotically and mitotically stable inheritance of DNA hypomethylation induced by ddm1 mutation of Arabidopsis thaliana. Genetics 1999;151:831–8. [32] Chan SW, Henderson IR, Zhang X, Shah G, Chien JS, Jacobsen SE. RNAi, DRD1, and histone methylation actively target developmentally important non-CG DNA methylation in arabidopsis. PLoS Genet 2006;2:e83. [33] Lindroth AM, Shultis D, Jasencakova Z, Fuchs J, Johnson L, Schubert D, et al. Dual histone H3 methylation marks at lysines 9 and 27 required for interaction with CHROMOMETHYLASE3. EMBO J 2004;23:4286–96. [34] Woo HR, Pontes O, Pikaard CS, Richards EJ. VIM1, a methylcytosinebinding protein required for centromeric heterochromatinization. Genes Dev 2007;21:267–77. [35] Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA, et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 2007;450:908–12. [36] Bostick M, Kim JK, Esteve PO, Clark A, Pradhan S, Jacobsen SE. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 2007;317:1760–4. [37] Citterio E, Papait R, Nicassio F, Vecchi M, Gomiero P, Mantovani R, et al. Np95 is a histone-binding protein endowed with ubiquitin ligase activity. Mol Cell Biol 2004;24:2526–35. [38] Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum Mol Genet 2005;14(spec no 1):R47–58. [39] Sasaki H, Matsui Y. Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet 2008;9:129–40. [40] Soppe WJ, Jacobsen SE, Alonso-Blanco C, Jackson JP, Kakutani T, Koornneef M, et al. The late flowering phenotype of fwa mutants is caused by gainof-function epigenetic alleles of a homeodomain gene. Mol Cell 2000;6: 791–802. [41] Kakutani T. Genetic characterization of late-flowering traits induced by DNA hypomethylation mutation in Arabidopsis thaliana. Plant J 1997;12:1447–51. [42] Oakeley EJ, Podesta A, Jost JP. Developmental changes in DNA methylation of the two tobacco pollen nuclei during maturation. Proc Natl Acad Sci USA 1997;94:11721–5. [43] Zluvova J, Janousek B, Vyskot B. Immunohistochemical study of DNA methylation dynamics during plant development. J Exp Bot 2001;52:2265–73. [44] Cao X, Jacobsen SE. Role of the arabidopsis DRM methyltransferases in de novo DNA methylation and gene silencing. Curr Biol 2002;12:1138–44. [45] Lindroth AM, Cao X, Jackson JP, Zilberman D, McCallum CM, Henikoff S, et al. Requirement of CHROMOMETHYLASE3 for maintenance of CpXpG methylation. Science 2001;292:2077–80. [46] Bartee L, Malagnac F, Bender J. Arabidopsis cmt3 chromomethylase mutations block non-CG methylation and silencing of an endogenous gene. Genes Dev 2001;15:1753–8. [47] Papa CM, Springer NM, Muszynski MG, Meeley R, Kaeppler SM. Maize chromomethylase Zea methyltransferase2 is required for CpNpG methylation. Plant Cell 2001;13:1919–28.

H. Saze / Seminars in Cell & Developmental Biology 19 (2008) 527–536 [48] Sarraf SA, Stancheva I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol Cell 2004;15:595–605. [49] Fujita N, Watanabe S, Ichimura T, Tsuruzoe S, Shinkai Y, Tachibana M, et al. Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression. J Biol Chem 2003;278:24132–8. [50] Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T. The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 2003;278:4035–40. [51] Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet 1999;23:58–61. [52] Fuks F, Hurd PJ, Deplus R, Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 2003;31:2305–12. [53] Esteve PO, Chin HG, Smallwood A, Feehery GR, Gangisetty O, Karpf AR, et al. Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev 2006;20:3089–103. [54] Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 2000;24:88–91. [55] Mathieu O, Probst AV, Paszkowski J. Distinct regulation of histone H3 methylation at lysines 27 and 9 by CpG methylation in Arabidopsis. EMBO J 2005;24:2783–91. [56] Tariq M, Saze H, Probst AV, Lichota J, Habu Y, Paszkowski J. Erasure of CpG methylation in Arabidopsis alters patterns of histone H3 methylation in heterochromatin. Proc Natl Acad Sci USA 2003;100:8823–7. [57] Soppe WJ, Jasencakova Z, Houben A, Kakutani T, Meister A, Huang MS, et al. DNA methylation controls histone H3 lysine 9 methylation and heterochromatin assembly in Arabidopsis. EMBO J 2002;21:6549–59. [58] Malagnac F, Bartee L, Bender J. An Arabidopsis SET domain protein required for maintenance but not establishment of DNA methylation. EMBO J 2002;21:6842–52. [59] Jackson JP, Lindroth AM, Cao X, Jacobsen SE. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 2002;416:556–60. [60] Ebbs ML, Bender J. Locus-specific control of DNA methylation by the Arabidopsis SUVH5 histone methyltransferase. Plant Cell 2006;18:1166–76. [61] Naumann K, Fischer A, Hofmann I, Krauss V, Phalke S, Irmler K, et al. Pivotal role of AtSUVH2 in heterochromatic histone methylation and gene silencing in Arabidopsis. EMBO J 2005;24:1418–29. [62] Johnson LM, Bostick M, Zhang X, Kraft E, Henderson I, Callis J, et al. The SRA methyl-cytosine-binding domain links DNA and histone methylation. Curr Biol 2007;17:379–84. [63] Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 2007;14:1025–40. [64] Klose RJ, Kallin EM, Zhang Y. JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 2006;7:715–27. [65] Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003;33(Suppl):245–54. [66] Jeddeloh JA, Stokes TL, Richards EJ. Maintenance of genomic methylation requires a SWI2/SNF2-like protein. Nat Genet 1999;22:94–7. [67] Brzeski J, Jerzmanowski A. Deficient in DNA methylation 1 (DDM1) defines a novel family of chromatin-remodeling factors. J Biol Chem 2003;278:823–8. [68] Dennis K, Fan T, Geiman T, Yan Q, Muegge K. Lsh, a member of the SNF2 family, is required for genome-wide methylation. Genes Dev 2001;15:2940–4. [69] Zhu H, Geiman TM, Xi S, Jiang Q, Schmidtmann A, Chen T, et al. Lsh is involved in de novo methylation of DNA. EMBO J 2006;25:335–45. [70] Tamaru H, Selker EU. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 2001;414:277–83. [71] Sollars V, Lu X, Xiao L, Wang X, Garfinkel MD, Ruden DM. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat Genet 2003;33:70–4. [72] Vastenhouw NL, Brunschwig K, Okihara KL, Muller F, Tijsterman M, Plasterk RH. Gene expression: long-term gene silencing by RNAi. Nature 2006;442:882. [73] Simpson VJ, Johnson TE, Hammen RF. Caenorhabditis elegans DNA does not contain 5-methylcytosine at any time during development or aging. Nucleic Acids Res 1986;14:6711–9. [74] Patel CV, Gopinathan KP. Determination of trace amounts of 5-methylcytosine in DNA by reverse-phase high-performance liquid chromatography. Anal Biochem 1987;164:164–9. [75] Annunziato AT. Split decision: what happens to nucleosomes during DNA replication? J Biol Chem 2005;280:12065–8. [76] Eitoku M, Sato L, Senda T, Horikoshi M. Histone chaperones: 30 years from isolation to elucidation of the mechanisms of nucleosome assembly and disassembly. Cell Mol Life Sci 2008;65:414–44. [77] Martin C, Zhang Y. Mechanisms of epigenetic inheritance. Curr Opin Cell Biol 2007;19:266–72. [78] Tagami H, Ray-Gallet D, Almouzni G, Nakatani Y. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 2004;116:51–61.

535

[79] Natsume R, Eitoku M, Akai Y, Sano N, Horikoshi M, Senda T. Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4. Nature 2007;446:338–41. [80] Henikoff S, McKittrick E, Ahmad K. Epigenetics, histone H3 variants, and the inheritance of chromatin states. Cold Spring Harb Symp Quant Biol 2004;69:235–43. [81] Henikoff S. Nucleosome destabilization in the epigenetic regulation of gene expression. Nat Rev Genet 2008;9:15–26. [82] Ng RK, Gurdon JB. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription. Nat Cell Biol 2008;10:102–9. [83] Aravin AA, Bourc’his D. Small RNA guides for de novo DNA methylation in mammalian germ cells. Genes Dev 2008;22:970–5. [84] Grewal SI, Jia S. Heterochromatin revisited. Nat Rev Genet 2007;8:35–46. [85] Kanno T, Bucher E, Daxinger L, Huettel B, Bohmdorfer G, Gregor W, et al. A structural-maintenance-of-chromosomes hinge domain-containing protein is required for RNA-directed DNA methylation. Nat Genet 2008;40:670–5. [86] Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F. RNAmediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 2006;441:469–74. [87] Voinnet O. Non-cell autonomous RNA silencing. FEBS Lett 2005;579:5858–71. [88] Fukuhara T, Koga R, Aoki N, Yuki C, Yamamoto N, Oyama N, et al. The wide distribution of endornaviruses, large double-stranded RNA replicons with plasmid-like properties. Arch Virol 2006;151:995–1002. [89] Moriyama H, Horiuchi H, Nitta T, Fukuhara T. Unusual inheritance of evolutionarily-related double-stranded RNAs in interspecific hybrid between rice plants Oryza sativa and Oryza rufipogon. Plant Mol Biol 1999;39:1127–36. [90] Whitelaw E, Martin DI. Retrotransposons as epigenetic mediators of phenotypic variation in mammals. Nat Genet 2001;27:361–5. [91] Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E. Metastable epialleles in mammals. Trends Genet 2002;18:348–51. [92] Chandler VL. Paramutation: from maize to mice. Cell 2007;128:641–5. [93] Alleman M, Sidorenko L, McGinnis K, Seshadri V, Dorweiler JE, White J, et al. An RNA-dependent RNA polymerase is required for paramutation in maize. Nature 2006;442:295–8. [94] Hale CJ, Stonaker JL, Gross SM, Hollick JB. A novel Snf2 protein maintains trans-generational regulatory states established by paramutation in maize. PLoS Biol 2007;5:2156–65. [95] Steimer A, Amedeo P, Afsar K, Fransz P, Mittelsten Scheid O, Paszkowski J. Endogenous targets of transcriptional gene silencing in Arabidopsis. Plant Cell 2000;12:1165–78. [96] Hirochika H, Okamoto H, Kakutani T. Silencing of retrotransposons in arabidopsis and reactivation by the ddm1 mutation. Plant Cell 2000;12: 357–69. [97] Miura A, Yonebayashi S, Watanabe K, Toyama T, Shimada H, Kakutani T. Mobilization of transposons by a mutation abolishing full DNA methylation in Arabidopsis. Nature 2001;411:212–4. [98] Singer T, Yordan C, Martienssen RA. Robertson’s Mutator transposons in A. thaliana are regulated by the chromatin-remodeling gene Decrease in DNA Methylation (DDM1). Genes Dev 2001;15:591–602. [99] Lippman Z, May B, Yordan C, Singer T, Martienssen R. Distinct mechanisms determine transposon inheritance and methylation via small interfering RNA and histone modification. PLoS Biol 2003;1:E67. [100] Kato M, Miura A, Bender J, Jacobsen SE, Kakutani T. Role of CG and nonCG methylation in immobilization of transposons in Arabidopsis. Curr Biol 2003;13:421–6. [101] Yi H, Riddle NC, Stokes TL, Woo HR, Richards EJ. Induced and natural epigenetic variation. Cold Spring Harb Symp Quant Biol 2004;69:155–9. [102] Stokes TL, Kunkel BN, Richards EJ. Epigenetic variation in Arabidopsis disease resistance. Genes Dev 2002;16:171–82. [103] Chan SW, Zhang X, Bernatavichute YV, Jacobsen SE. Two-step recruitment of RNA-directed DNA methylation to tandem repeats. PLoS Biol 2006;4:e363. [104] Kinoshita T, Miura A, Choi Y, Kinoshita Y, Cao X, Jacobsen SE, et al. One-way control of FWA imprinting in Arabidopsis endosperm by DNA methylation. Science 2004;303:521–3. [105] Fujimoto R, Kinoshita Y, Kawabe A, Kinoshita T, Takashima K, Nordborg M, et al. Evolution and control of imprinted FWA genes in the genus Arabidopsis. PLoS Genet 2008;4:e1000048. [106] Kinoshita Y, Saze H, Kinoshita T, Miura A, Soppe WJ, Koornneef M, et al. Control of FWA gene silencing in Arabidopsis thaliana by SINE-related direct repeats. Plant J 2007;49:38–45. [107] Ikeda Y, Kobayashi Y, Yamaguchi A, Abe M, Araki T. Molecular basis of lateflowering phenotype caused by dominant epi-alleles of the FWA locus in Arabidopsis. Plant Cell Physiol 2007;48:205–20. [108] Chan SW, Zilberman D, Xie Z, Johansen LK, Carrington JC, Jacobsen SE. RNA silencing genes control de novo DNA methylation. Science 2004;303:1336. [109] Jacobsen SE, Sakai H, Finnegan EJ, Cao X, Meyerowitz EM. Ectopic hypermethylation of flower-specific genes in Arabidopsis. Curr Biol 2000;10:179–86. [110] Jacobsen SE, Meyerowitz EM. Hypermethylated SUPERMAN epigenetic alleles in arabidopsis. Science 1997;277:1100–3. [111] Johnson L, Cao X, Jacobsen S. Interplay between two epigenetic marks. DNA methylation and histone H3 lysine 9 methylation. Curr Biol 2002;12:1360–7. [112] Zilberman D, Cao X, Jacobsen SE. ARGONAUTE4 control of locus-specific siRNA accumulation and DNA and histone methylation. Science 2003;299: 716–9.

536

H. Saze / Seminars in Cell & Developmental Biology 19 (2008) 527–536

[113] Saze H, Kakutani T. Heritable epigenetic mutation of a transposon-flanked Arabidopsis gene due to lack of the chromatin-remodeling factor DDM1. EMBO J 2007;26:3641–52. [114] Mathieu O, Reinders J, Caikovski M, Smathajitt C, Paszkowski J. Transgenerational stability of the Arabidopsis epigenome is coordinated by CG methylation. Cell 2007;130:851–62. [115] McClintock B. The significance of responses of the genome to challenge. Science 1984;226:792–801. [116] Grandbastien MA, Audeon C, Bonnivard E, Casacuberta JM, Chalhoub B, Costa AP, et al. Stress activation and genomic impact of Tnt1 retrotransposons in Solanaceae. Cytogenet Genome Res 2005;110:229–41. [117] Takeda S, Sugimoto K, Otsuki H, Hirochika H. Transcriptional activation of the tobacco retrotransposon Tto1 by wounding and methyl jasmonate. Plant Mol Biol 1998;36:365–76. [118] Hashida SN, Uchiyama T, Martin C, Kishima Y, Sano Y, Mikami T. The temperature-dependent change in methylation of the Antirrhinum transposon Tam3 is controlled by the activity of its transposase. Plant Cell 2006;18:104–18. [119] Lukens LN, Zhan S. The plant genome’s methylation status and response to stress: implications for plant improvement. Curr Opin Plant Biol 2007;10:317–22. [120] Ries G, Buchholz G, Frohnmeyer H, Hohn B. UV-damage-mediated induction of homologous recombination in Arabidopsis is dependent on photosynthetically active radiation. Proc Natl Acad Sci USA 2000;97:13425–9. [121] Lucht JM, Mauch-Mani B, Steiner HY, Metraux JP, Ryals J, Hohn B. Pathogen stress increases somatic recombination frequency in Arabidopsis. Nat Genet 2002;30:311–4. [122] Molinier J, Ries G, Zipfel C, Hohn B. Transgeneration memory of stress in plants. Nature 2006;442:1046–9. [123] Cubas P, Vincent C, Coen E. An epigenetic mutation responsible for natural variation in floral symmetry. Nature 1999;401:157–61.

[124] Manning K, Tor M, Poole M, Hong Y, Thompson AJ, King GJ, et al. A naturally occurring epigenetic mutation in a gene encoding an SBP-box transcription factor inhibits tomato fruit ripening. Nat Genet 2006;38: 948–52. [125] Zhai J, Liu J, Liu B, Li P, Meyers BC, Chen X, et al. Small RNA-directed epigenetic natural variation in Arabidopsis thaliana. PLoS Genet 2008;4:e1000056. [126] Vaughn MW, Tanurd Ic M, Lippman Z, Jiang H, Carrasquillo R, Rabinowicz PD, et al. Epigenetic Natural Variation in Arabidopsis thaliana. PLoS Biol 2007;5: e174. [127] Rangwala SH, Elumalai R, Vanier C, Ozkan H, Galbraith DW, Richards EJ. Meiotically stable natural epialleles of Sadhu, a novel Arabidopsis retroposon. PLoS Genet 2006;2:e36. [128] Rangwala SH, Richards EJ. Differential epigenetic regulation within an Arabidopsis retroposon family. Genetics 2007;176:151–60. [129] Bender J. DNA methylation of the endogenous PAI genes in Arabidopsis. Cold Spring Harb Symp Quant Biol 2004;69:145–53. [130] Saze H, Shiraishi A, Miura A, Kakutani T. Control of genic DNA methylation by a jmjC domain-containing protein in Arabidopsis thaliana. Science 2008;319:462–5. [131] Yu X, Li L, Li L, Guo M, Chory J, Yin Y. Modulation of brassinosteroid-regulated gene expression by jumonji domain-containing proteins ELF6 and REF6 in Arabidopsis. Proc Natl Acad Sci USA 2008;105:7618–23. [132] Liu F, Quesada V, Crevillen P, Baurle I, Swiezewski S, Dean C. The Arabidopsis RNA-binding protein FCA requires a lysine-specific demethylase 1 homolog to downregulate FLC. Mol Cell 2007;28:398–407. [133] Penterman J, Zilberman D, Huh JH, Ballinger T, Henikoff S, Fischer RL. DNA demethylation in the Arabidopsis genome. Proc Natl Acad Sci USA 2007;104:6752–7. [134] Zhu J, Kapoor A, Sridhar VV, Agius F, Zhu JK. The DNA glycosylase/lyase ROS1 functions in pruning DNA methylation patterns in Arabidopsis. Curr Biol 2007;17:54–9.