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Curr Opin Plant Biol. Author manuscript; available in PMC Oct 1, 2011.
Published in final edited form as:
PMCID: PMC3097131
NIHMSID: NIHMS294057

Epigenetic modifications in plants: an evolutionary perspective

Abstract

Plant genomes are modified by an array of epigenetic marks that help regulate plant growth and reproduction. Although plants share many epigenetic features with animals and fungi, some epigenetic marks are unique to plants. In different organisms, the same epigenetic mark can play different roles and/or similar functions can be carried out by different epigenetic marks. Furthermore, while the enzymatic systems responsible for generating or eliminating epigenetic marks are often conserved, there are also cases where they are quite divergent between plants and other organisms. DNA methylation and methylation of histone tails on the lysine 4, 9 and 27 positions are among the best characterized epigenetic marks in both plants and animals. Recent studies have greatly enhanced our knowledge about the pattern of these marks in various genomes and provided insights into how they are established and maintained and how they function. This review focuses on the conservation and divergence of the pathways that mediate these four types of epigenetic marks.

Introduction

Plants show a high degree of developmental plasticity, partly due to their sessile way of life and the need to cope with a frequently changing environment. Recent studies show that epigenetic pathways (e.g. DNA methylation, histone variants and modifications, positioning of nucleosomes, and small RNA)[CH1] are important components of plant growth and reproduction regulation [1••]. Multiple aspects of plant development, including flowering time, gametogenesis, stress response, light signaling, and morphological change are modulated directly or indirectly by epigenetic marks. Plants have acquired complex systems to regulate the epigenetic marks on their genomic DNA, some of which are conserved from other organisms such as animals and insects, and some of which are specific for plants.

In the genomes of higher plants, 5-methyl cytosine methylation is widely found, bearing the important function of defense against activation and movement of transposable elements and expression regulation of certain developmental genes. DNA methylation is conserved in many other eukaryotic organisms, albeit with clear divergence in the methylation enzyme systems and functions [2••,3••,4••]. Other common epigenetic marks consist of modifications on histone tails. Unlike DNA methylation that invariably takes place at the carbon-5 position of cytosine residues, different histones (H2A, H2B, H3 and H4) can be covalently modified at different positions (mostly lysine and arginine residues) by different chemical marks (methylation, acetylation, ubiquitination, phosphorylation, biotinylation and ADP-ribosylation) [5,6]. Different histone marks have different functions, and even the same histone mark can have different functions in different organisms. Three types of histone methylation in plants, histone H3K4 mono/di/tri-methylation (H3K4me1, H3K4me2 and H3K4me3), histone H3K27 tri-methylation (H3K27me3) and histone H3K9 di-methylation (H3K9me2), are the most well-studied representatives to consider the evolution of plant epigenetic modification systems.

H3K4 mono/di/tri-methylation

Lysines are capable of accepting three methyl groups, meaning that a given lysine residue on histone can be mono-methylated, di-methylated or tri-methylated. In the case of H3K4 in Arabidopsis, these three methylated forms are all detected by mass spectrometry analysis [6]. Genome-wide profiling of Arabidopsis H3K4me1, H3K4me2 and H3K4me3 by ChIP-chip demonstrated that they exist exclusively in genes and promoters (~2/3 of all genes) and are essentially absent from heterochromatic regions where transposons and repetitive DNA reside (Table 1 and Figure 1), consistent with the notion that H3K4 methylation marks the active chromatin [7••]. Within genes, the distributions of the three H3K4 marks are different – H3K4me1 is enriched in the body of the genes with depletion on both ends of the genes, while H3K4me2 and H3K4me3 are enriched in the promoter and 5′-end of genes with H3K4me3 being further upstream of H3K4me2 (Figure 1). Furthermore, only H3K4me3 is associated with active transcription while H3K4me1 and H3K4me2 are not well correlated with transcription [7••].

Figure 1
Schematic representation of the distribution of selected epigenetic marks in the Arabidopsis genome
Table 1
Epigenetic marks and corresponding players in Arabidopsis and human.

Similar distribution patterns of the three types of H3K4 methylation have been reported in other organisms, including rice, yeast, and human [8-12]. This suggests that the mechanism for H3K4 methylation is highly conserved. Yeast (Saccharomyces cerevisiae[CH2]) has a single H3K4 methyltransferase, termed SET1, which has a highly conserved SET (Su(var)3-9, Enhancer-of-zeste, and Trithorax[CH3]) domain (~150 amino acids). SET1 forms a complex called Complex Proteins Associated with Set 1 (COMPASS), which can mediate mono-methylation, di-methylation and tri-methylation of H3K4 [13]. In Drosophila, H3K4 methylation is mediated by homologs of yeast SET1, the Trithorax group (TrxG) proteins, which were first identified genetically as the counteractors of the Polycomb [CH4]group (PcG) proteins in controlling the expression of Homeotic (HOX) genes (see below) [14]. Another Drosophila H3K4 methyltransferase that also contains a SET domain is Absent, Small or Homeotic Disc 1 (Ash1), which was suggested to be the main enzyme responsible for di-methylating H3K4 [15]. Mammals methylate H3K4 by COMPASS-like complexes that contain various TRX-family proteins, as well as Ash1 [16,17] (Table 1). SET-domain H3K4 methyltransferases are also found in Arabidopsis, in the form of five Arabidopsis TRX proteins, ARABIDOPSIS HOMOLOG OF TRITHORAX 1 (ATX1) to ATX5; as well as seven ARABIDOPSIS TRITHORAX-RELATED (ATXR) proteins, ATXR1 to ATXR7; and seven ASH1 homologs, ASH1 HOMOLOG 1 (ASHH1) to ASHH4, and ASH1-RELATED 1 (ASHR1) to ASHR3 [18] (Table 1). Among them, ATX1 and ATX2 are the best studied. These two proteins appear to play quite divergent roles despite their highly similar protein sequence (~65% identical). For instance, they regulate the transcription of two largely non-overlapping sets of genes [19,20]. It has been shown at some loci that H3K4me3 is mediated by ATX1 whereas H3K4me2 is mediated by ATX2 [20•,21]. Moreover, ASHH2, also known as EARLY FLOWERING IN SHORT DAYS (EFS) and SET DOMAIN GROUP 8 (SDG8), is a dual function histone methyltransferase for both H3K4 and H3K36 [22•]. Most recently, ATXR3, also known as SDG2, has been demonstrated to be the major H3K4 tri-methyltransferase in Arabidopsis [23•,24•]. Overall, it is clear that H3K4 methylation systems are evolutionarily ancient and that plants and other eukaryotes likely share a common ancestral mechanism. However, it is also clear that certain TRX-related proteins have acquired other functions in plants. For example, ATXR5 and ATXR6 are two methyltransferases for H3K27 mono-methylation (a repressive mark for silencing transposons) and their SET domains are quite diverged from the ones present in SET1 homologs. Interestingly, this methylation also appears to regulate DNA replication in heterochromatin [25•].

H3K27 tri-methylation

Another abundant histone modification in Arabidopsis is H3K27 tri-methylation [5,6]. H3K27me3 has been extensively studied in Arabidopsis, as well as in many other organisms, as a major repressive mark for gene expression. Several well-known Arabidopsis developmental genes, including flower timing gene FLOWERING LOCUS C (FLC), floral organ patterning gene AGAMOUS (AG), homeobox gene SHOOT MERISTEMLESS (STM), and two imprinted genes MEDEA (MEA) and PHERES1 (PHE1), are epigenetically silenced by H3K27me3 [26,27]. Recently, many more H3K27me3 target genes (~4400) have been revealed by whole-genome ChIP-chip analysis in Arabidopsis [28••] (Table 1). These genes are enriched for transcription factors, supporting an important role of H3K27me3 in plant development. The expression levels of the H3K27me3 modified genes are very low and often exhibit a high degree of tissue specificity (with the majority of them only expressed in one or a few tissues), which suggests repression of these genes by H3K27me3 is alleviated only in the place where their expression is needed. Interestingly, H3K27me3-modified regions in Arabidopsis are generally limited to the length of a single gene and two or more adjacent genes controlled by the same patch of H3K27me3 is very rarely seen [28••] (Figure 1). This is in contrast to the long-range spreading and very large patches of H3K27me3 that is common in Drosophila and mammals [29-31].

This difference might be attributed to the divergence of H3K27 tri-methylation systems in plants versus other organisms. All organisms that have H3K27me3 contain Polycomb group proteins (PcG). Like TrxG proteins, PcG proteins were also first identified through genetic analysis in Drosophila due to their effect (repressive, as opposed to the activation role of TrxG) on HOX genes [32]. Several protein complexes are formed by PcG, namely Polycomb Repressive Complex 1 (PRC1), PRC2, and PhoRC [33]. PRC2 contains a key subunit called Enhancer of zeste, E(z), which is a SET domain histone methyltransferase specific for H3K27 tri-methylation. Arabidopsis has three E(z) homologs, CURLY LEAF (CLF), MEA and SWINGER (SWN), as well as homologs for each of the other subunits of PRC2 [26,27] (Table 1). It therefore seems likely that PRC2 was present in the last common ancestor of plants and animals. However, the Arabidopsis genome does not seem to encode components for PRC1 or PhoRC, suggesting that these two complexes are either lost in the plant lineage or have evolved independently in animals. Considering the implicated role of PRC1 in recognizing and assisting in the spread of H3K27me3 [34], the absence of PRC1 in plants might explain why the average length of H3Kk27me3-modified regions in Arabidopsis is a few kilobases as opposed to hundreds of kilobases seen in Drosophila and mammals [28••]. Nonetheless, plants must have systems that recognize the H3K27me3 mark in order for it affect gene expression. Several PRC1-like activities have been reported in Arabidopsis. A plant chromodomain protein, LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), has been found to bind H3K27me3 in vitro (through its chromodomain) and colocalize with H3K27me3 genome-wide in planta [35••,36••], which is analogous to the function of the chromodomain protein Polycomb (Pc) in the PRC1 complex. Other proteins that have been reported to substitute PRC1 functions in Arabidopsis include VERNALIZATION 1 (VRN1) [37], EMBRYONIC FLOWER 1 (EMF1) [38] and AtRING1a and AtRING1b [39,40]. This functional diversification may lead to different outcomes for PcG-regulated genes in plants, and this area deserves further study.

H3K9 di-methylation

In eukaryotes, heterochromatin is distinguished from euchromatin in that it is densely compacted, transcriptionally inactive, and contains methylated DNA, histones with repressive marks and deacetylated histones. In animals and fungi, the formation of heterochromatin is in part dependent on the methylation of H3K9 and the interaction between methylated H3K9 and Heterochromatin Protein 1 (HP1) that contains a chromodomain for binding methylated histones [41-44]. In general, H3K9 tri-methylation is a mark of heterochromatin (e.g. in Neurospora crasssa and mammals); however, H3K9me3 of Arabidopsis is typically localized in euchromatin [36••]. Instead, the pre-dominant mark for heterochromatin in Arabidopsis is H3K9 di-methylation [45] (Table 1 and Figure 1). Recent genomic profiling studies using ChIP-chip in Arabidopsis show that H3K9me2 is highly enriched in pericentromeric heterochromatin as large and uninterrupted blocks and also exists in euchromatic repeats and transposons as small patches that cover the respective repeat/transposon unit, consistent with the notion that it labels the silenced chromatin [46••] (Figure 1). H3K9me2-modified regions are tightly correlated with regions in the Arabidopsis genome that contain CHG (where H is A, C or T) methylation (a type of DNA methylation almost exclusively found in higher plants; see below) [46••].

The enzymes for methylating H3K9, the Su(var)3-9 family proteins, were the first histone lysine methyltransferases reported [47]. The Su(var)3-9 locus, again, was initially identified through Drosophila genetics when searching for suppressors of position-effect variegation (PEV) [48]. The PEV suppressor screen also turned up Su(var)2-5 that encodes HP1. This was the initial indication that H3K9 methylation and HP1 likely functioned in the same pathway, which was later confirmed in many organisms [14]. Su(var)3-9 homologs have been shown in many organisms to play roles in heterochromatin formation and gene silencing, and a few examples include cryptic loci regulator 4 (Clr4) in yeast (S. pombe) and Suv39h proteins in mammals [42,49] (Table 1). Arabidopsis also has multiple Su(var)3-9 homologs called the SUVH proteins, and among them, KRYPTONITE (KYP, also known as SUVH4) is a mono- and di-methyltransferase for H3K9 that is required for the presence of H3K9me2 in heterochromatin [50,51]. Two other SUVH proteins, SUVH5 and SUVH6, also methylate H3K9 [50,52,53] (Table 1). Although plants are similar to animals and fungi in that they utilize Su(var)3-9 family proteins for H3K9 methylation, plants have a very unique mechanism for the maintenance and function of H3K9 methylation. As mentioned above, the HP1 homolog in Arabidopsis, LHP1, recognizes and co-localizes with H3K27 tri-methylation but not H3K9 methylation [35••]. Arabidopsis H3K9me2 is instead bound by a different chromodomain-containing protein called CHROMOMETHYLASE 3 (CMT3), which is a maintenance DNA methyltransferase for CHG sites. Consistently, loss of KYP leads to reduction in both H3K9me2 and CHG methylation levels, suggesting H3K9me2 controls CHG methylation [51,54]. Moreover, the SRA (SET and RING-Associated) domain of KYP has been shown to bind DNA with methylated CHG sites, suggesting that DNA methylation recruits histone methyltransferase [55]. These findings support a self-reinforcing feedback model between KYP and CMT3 that efficiently maintains H3K9 methylation and CHG methylation in heterochromatic regions. A similar mechanism has been discovered in Neurospora, where H3K9me3 directs DNA methylation. However, it differs from the system in plants in two key aspects. First it requires HP1 to act as an adapter between the histone H3K9 methyltransferase Defective in Methylation 5 (DIM-5) and the DNA methyltransferase DIM-2. Second, histone methylation is strictly upstream of DNA methylation and there is therefore no feedback loop as for Arabidopsis [56].

DNA methylation

Cytosine methylation is a common modification found in genomes of plants, animals, and fungi. For instance, model organisms used for biological studies such as Arabidopsis, Neurospora, human, mouse, rice, and zebrafish contain abundant amount of methylated cytosines. However, DNA methylation has been curiously lost in some other well studied model organisms including Caenorhabditis elegans[CH5], Drosophila, baker’s yeast and fission yeast [57••]. Cytosines are methylated in a variety of DNA sequences contexts, but mechanistically can be classified broadly into three contexts, CG, CHG (H = A, T, C) and CHH [2••]. Because methylated cytosines behave the same way as unmethylated cytosines during standard DNA sequencing reactions, genome sequencing projects do not provide DNA methylation information. This can be overcome by sodium bisulfite treatment which converts unmethylated cytosines to uracils but does not alter methylated cytosines [58••,59••]. One complication in assaying DNA methylation is that it is highly variable even within the same cell type, which means that a particular cytosine position can show a different methylation status from one cell to another. Therefore, multiple (usually >10) sequenced clones covering the same cytosine are needed to obtain an overall picture of the methylation status for a given cytosine position (on either the Watson or Crick strand). With the recent advancement in high-throughput sequencing, high coverage methylation maps of eukaryotic genomes have started to emerge [58••,59••].

Arabidopsis has perhaps the most extensively characterized methylome of any organism. Due to its small genome size and important role as a model system, Arabidopsis has become the first organism where a whole-genome tiling array analysis of DNA methylation and a whole-genome single nucleotide resolution DNA methylation map were published [58••,59••,60]. Two general patterns of DNA methylation are evident in the Arabidopsis genome. The first is high levels of methylation in all three cytosine contexts (CG, CHG and CHH) on transposable elements (TEs) and other repetitive DNA, which are mostly found in pericentromeric heterochromatic regions but also exist in small patches between genes in the euchromatic arms. The second is methylation in the transcribed region or body of genes (excluded from both ends and assuming a bell-like shape with a slight bias toward the 3′-half). This gene body methylation is found in ~1/3 of all protein-coding genes and takes place exclusively in the CG context [58••,59••-63] (Table 1 and Figure 1). Functionally, these two types of methylation play two very different roles. Methylation on TEs and repeats represses the transcription of these DNAs as a genome defense mechanism against selfish DNA. On the other hand, gene body methylation somewhat positively correlates with gene transcription levels, with the highest methylation level observed in genes with moderately high transcription [4••,60,62]. Genes with tri-methylated H3K27 generally do not have DNA methylation, indicating the anti-correlation of these two epigenetic marks [28••] (Figure 1).

Recent whole genome methylation analysis of a variety of eukaryotic organisms allows an examination of these two general patterns of methylation from an evolutionary perspective [3••,4••,57••]. Preferential methylation of TEs and repeats has long been considered to be ancient, and perhaps the primary reason for the existence of DNA methylation [64]. However, TE methylation was not found in a number of invertebrate animals, including insects such as honeybee and silk moth, sea anemone and sea squirt; yet, these organisms show a clear preference for methylation within gene bodies [3••,4••]. Most plants and fungi, on the other hand, clearly preferentially methylate their TEs and repeats. Gene body methylation is found in both animals and plants, but not in fungi, suggesting that this may be an ancient methylation pattern that was subsequently lost in fungi. Vertebrate animals show both gene body methylation and transposon methylation. However, vertebrate genomes are so highly CG methylated (~85%) that it is somewhat difficult to assess whether TEs and repeats are preferentially methylated over the rest of the genome [3••,4••]. These considerations suggest that gene body methylation is likely to be at least as ancient as the TE and repeat methylation, both of which would be predicted to be present in the last common ancestor of animals, fungi and plants.

Some algal species show unique patterns of methylation. Chlorella [CH6]methylation patterns basically mimic those of vertebrates both at genome-wide levels and within the body of genes. Volvox [CH7]on the other hand has very low levels of methylation overall, but like higher plants shows methylation of both genes and repeats [4••]. Chlamydomonas [CH8]is unusual because it displays preferential methylation of genes in all three sequence contexts, instead of just in a CG context as found in most other organism; and it displays transposon methylation in a CG only context, instead of in all sequence contexts [3••].

The function of gene body methylation is unclear since its loss in methylation mutants has only subtle effects on overall levels of gene expression [60,62]. However, the recent finding that methylation is much more prevalent on exons than on introns suggests that methylation may contribute to exon definition or regulate alternative splicing [3••,65•,66••]. Although it is an attractive hypothesis that methylation may regulate splicing, experimental support for this idea is generally lacking, and understanding the function of gene body methylation is an important future endeavor.

The eukaryotic cytosine methyltransferase enzymes which methylate DNA are homologous to bacterial restriction modification methyltransferases, revealing their very ancient origin [67]. The activity of DNA methyltransferases can be broadly classified into that which establishes methylation on previously unmethylated DNA (de novo methylation) and that which maintains preexisting methylation (maintenance methylation). De novo methylation in mammal and plants are mostly carried out through the DNA (cytosine-5)-methyltransferase 3 (Dnmt3) class of enzymes, called DOMAIN REARRANGED METHYLTRANSFERASE 2 (DRM2) in plants (Table 1) [2••]. However, the mechanism by which these enzymes are targeted is very different. Dnmt3 class enzymes in mammals are targeted in large part by binding to histone H3 tails which are unmethylated at lysine 4, which could help explain why mammalian genomes are heavily methylated except at the CpG-rich promoters of genes which are high in H3K4 methylation [1••,68]. In addition, DRM2 de novo methylation activity is targeted to DNA by small interfering RNAs (siRNAs) in a very complex pathway termed RNA-directed DNA methylation (RdDM) [2••]. Although an RdDM-like pathway does not exist in mammals, a close one is the PIWI-associated RNA (piRNA) pathway that guides Dnmt3 activity in mouse germ cells [69].

As proposed by Arthur Riggs more than 35 years ago [70], maintenance methylation relies at least in part on the symmetry of the CG and CHG sites. For the maintenance of CG methylation, the mechanism appears to be highly conserved, at least in plants and vertebrates. The CG maintenance DNA methyltransferase is high conserved and found in all plants animals and fungi. For instance Dnmt1 of mammals and METHYLTRANSFERASE 1 (MET1) (Table 1) from Arabidopsis appear to be orthologous and are similar in function. Mutations in both lead to dramatic losses of CG DNA methylation (in Arabidopsis this loss is complete) [58••,59••,67]. In addition, both function with a conserved cofactor called Ubiquitin-like Containing PHD and RING Finger Domains 1 (UHRF1) in mammals and VARIATION IN METHYLATION (VIM) in Arabidopsis [2••]. This cofactor contains an SRA domain which binds methylated DNA, and the SRA of UHRF1 has been demonstrated to recognize hemimethylated DNA, the physiological substrate for Dnmt1 which is produced at DNA replication foci [55,71-73].

CHG is also a symmetrical site, but the mechanism by which this methylation is maintained differs in plants and other organisms. As discussed above, plants maintain high levels of CHG methylation through a self-reinforcing feed-forward loop between the CMT3 DNA methyltransferase and the KYP H3K9m2 methyltransferase. Mammals have low amounts of CHG methylation, except in ES cells where it is clearly detectable along with CHH methylation. However, this CHG methylation is ‘asymmetrical’, meaning that CHG sites are usually only methylated only on one strand, and moreover, CHG and CHH methylation are of roughly similar levels, suggesting that they may be maintained by the same mechanism, probably through Dnmt3 activity [74••] (Table 1). CMT family methyltransferases are found only in plants and algae, where abundant CHG methylation is observed [3••,4••]. Fungal DIM-2 has similar functions to CMT3 in that it is also guided by histone H3K9 methylation (see above); however, DIM-2 does not appear to be specific for CHG but rather methylates cytosines in all sequence contexts without any preference [56]. Both CMT and DIM-2 homologs are related to Dnmt1 but form a distinct group by themselves [57••].

CHH methylation is also maintained, but due to its asymmetric nature it has been long thought that this type of methylation is likely persistently targeted by de novo DNA methylation systems. Consistent with this idea, CHH methylation in mammals is dependent on Dnmt3 class enzymes, and CHH methylation in Arabidopsis is dependent on DRM2 and RdDM [2••].

Finally, although Dnmt1 enzymes are clearly the key maintenance methyltransferases for CG sites as discussed, some organisms such as algae and silk moth only have Dnmt1 but not Dnmt3 [3••,57••,67]. Interestingly, CHG and CHH methylation are readily detectable in the green algae [CH9]Chlamydomonas [CH10][3••]. Together, these findings suggest that Dnmt1 might have assumed a de novo methylation function and/or adopted activity toward non-CG sites in some organisms.

Conclusions and perspectives

The conservation and divergence of multiple epigenetic modification pathways in plants and other eukaryotic organisms have started to be revealed by genetic and genomic studies of a variety of organisms (Table 1). A general theme that emerges is that the epigenetic marks and the mechanisms that establish these marks are frequently ancient and conserved, but the precise details of how these marks function within genomes is often divergent. This functional divergence is likely due to the evolutionary forces that have adapted these epigenetic mechanisms to the needs of the specific organism. Another important factor not discussed in this review is the targeted erasure of epigenetic modifications, as exemplified by histone and DNA demethylases. These activities, which show their own conservation and divergence of mechanism [1••,75•], act in opposition to the establishment and maintenance mechanisms to shape dynamic epigenomic landscapes.

Acknowledgements

We thank Xiaoyu Zhang for critical reading and commenting on the manuscript. Research in the Jacobsen laboratory is supported by the National Institutes of Health (GM60398) and the National Science Foundation Genome Research Program (#0701745). Suhua Feng is a Special Fellow of the Leukemia & Lymphoma Society. Steve Jacobsen is an investigator of the Howard Hughes Medical Institute.

Footnotes

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