Key Points
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Recent studies have shown that RNA-directed DNA methylation (RdDM) in Arabidopsis thaliana not only requires the production of 24-nucleotide small interfering RNAs (siRNAs) and the de novo DNA methyltransferase DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) but also requires the production of RNA polymerase V (Pol V)-dependent intergenic non-coding (IGN) transcripts. Two crucial RdDM components, ARGONAUTE 4 (AGO4) and SUPPRESSOR OF TY INSERTION 5-LIKE (SPT5L), interact with Pol V-dependent transcripts, which suggests that they serve as a scaffold for the recruitment of the RdDM machinery. This process ultimately leads to DNA methylation and silencing at loci that produce siRNAs and IGN transcripts.
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Analyses of transposon expression and DNA methylation patterns in pollen grains and in embryo and endosperm tissues, respectively, suggest that genome-wide decreases in DNA methylation occur during male and female gametogenesis in A. thaliana, which might facilitate enhanced RdDM and transposon silencing in the sperm and egg cells by an unknown mechanism.
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Biochemical purification of DNA methyltransferase 3-like (DNMT3L) revealed an interaction between DNMT3L and unmethylated histone 3 lysine 4 (H3K4) tails. As DNMT3L also interacts with the DNMT3A de novo methyltransferase and because H3K4 methylation is anticorrelated with DNA methylation, a model has been proposed in which DNMT3L interaction with unmethylated H3K4 tails targets de novo methylation.
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Several recent findings suggest that Piwi-interacting RNAs (piRNAs) target de novo DNA methylation at transposons and other repetitive elements of the genome during male gametogenesis in mammals. piRNA populations isolated early in development were found to be enriched for such sequence elements, and mutations in MILI — a Piwi-clade Ago protein that binds piRNAs — showed DNA methylation defects at the stage of development at which de novo methylation is observed.
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Characterization of the Piwi clade of Ago proteins revealed the presence of symmetrical dimethylarginine modifications on several family members from Xenopus laevis, Drosophila melanogaster and mice. Tudor domains are known to interact with this modification, and Tudor domain-containing 1 (TDRD1), a protein with several Tudor domains, interacts with MILI and is required for DNA methylation and transposon silencing.
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In mammals, DNA methylation is maintained during DNA replication through the activity of DNMT1, which catalyses the methylation of hemimethylated CG sites in newly synthesized DNA. This activity depends heavily on the presence of ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1), a protein that specifically recognizes hemimethylated DNA and is proposed to recruit DNMT1 to chromatin.
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In A. thaliana, 5-methylcytosine DNA glycosylases and the base excision repair pathway catalyse active DNA demethylation during female gametogenesis and in vegetative plant tissues. Demethylation during gametogenesis is required for imprinting, whereas demethylation in vegetative tissues is proposed to combat robust DNA methylation by the RdDM pathway.
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In zebrafish there is evidence for an active DNA demethylation pathway that also involves DNA glycosylase activity and the base excision repair pathway. However, unlike in A. thaliana, in which methylated cytosines are directly recognized and removed, in zebrafish the methylated cytosine is first deaminated by the activation-induced cytosine deaminase (Aid)/apolipoprotein B mRNA-editing enzyme (Apobec) family of proteins, generating a G/T mismatch. This base is then removed by a thymine DNA glycosylase in what seems to be a tightly coupled manner.
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In mammals, mechanisms for active DNA demethylation remain unclear. However, an early model proposed a mechanism similar to that recently demonstrated in zebrafish, and a recent study showing that AID is necessary for the reduced levels of DNA methylation normally observed in primordial germ cells also supports this hypothesis. The discovery of the 5-hydroxymethylcytosine modification in certain mammalian cell types led to speculation that this modification could be a substrate for active DNA methylation.
Abstract
Cytosine DNA methylation is a stable epigenetic mark that is crucial for diverse biological processes, including gene and transposon silencing, imprinting and X chromosome inactivation. Recent findings in plants and animals have greatly increased our understanding of the pathways used to accurately target, maintain and modify patterns of DNA methylation and have revealed unanticipated mechanistic similarities between these organisms. Key roles have emerged for small RNAs, proteins with domains that bind methylated DNA and DNA glycosylases in these processes. Drawing on insights from both plants and animals should deepen our understanding of the regulation and biological significance of DNA methylation.
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Acknowledgements
We thank members of the Jacobsen laboratory and anonymous reviewers for useful comments and discussion. We apologize to colleagues whose research we did not have space to discuss, especially those studying DNA methylation in other systems, such as maize and Neurospora species. J.A.L. was supported the US National Institutes of Health National Research Service Award 5F32GM820453. This research was supported by US National Institutes of Health grant GM60398. S.E.J. is an investigator at the Howard Hughes Medical Institute.
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DATABASES
FURTHER INFORMATION
Glossary
- Epigenetic modifications
-
Chemical additions to DNA and histones that are associated with changes in gene expression and are heritable but do not alter the primary DNA sequence.
- Histones
-
The main protein components of chromatin. The four core histones, H2A, H2B, H3 and H4, form a globular octameric complex called a nucleosome upon which DNA is wrapped. The amino-terminal regions of histone proteins are largely unstructured and are subject to various chemical modifications, including methylation.
- CpG island
-
A sequence of at least 200 bp with a greater number of CpG sites than expected for its GC content. These regions are often GC rich, typically undermethylated, and are found upstream of many mammalian genes.
- RNA-directed DNA methylation
-
A plant-specific pathway through which small RNAs (24 nucleotides long) target the de novo methyltransferase DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) to homologous genomic loci to establish DNA methylation, which leads to transcriptional gene silencing.
- RNA interference
-
A process of post-transcriptional gene silencing in which small RNAs, often generated by the activity of an RNA-dependent RNA polymerase and a Dicer endoribonuclease, are bound by Argonaute proteins and target cleavage of homologous mRNA transcripts.
- Dicer
-
An RNase III family endonuclease that processes dsRNAs into small interfering RNAs.
- Argonautes
-
Effector proteins of small RNA-directed silencing. Small RNAs guide Argonautes to their RNA targets. Argonaute proteins are characterized by two domains PIWI (a ribonuclease domain) and Piwi Argonaute and Zwille (PAZ; an ssRNA-binding module).
- Chromatin-remodelling factors
-
Proteins that have the capacity to remodel chromatin, often using the energy of ATP, so that gene transcription can be activated or silenced.
- Small interfering RNAs
-
2025 nucleotide-long RNAs that are generated from dsRNAs and serve as guides for the cleavage of homologous mRNAs in RNA interference or for the addition of chromatin modifications, including histone and DNA methylation at homologous genomic sequences in transcriptional gene silencing.
- Cajal bodies
-
Nuclear bodies that are associated with the maturation of ribonucleoprotein complexes.
- Heterochromatin
-
A densely packaged form of chromatin that is associated with repressive histone modifications, DNA methylation and gene silencing.
- Primordial germ cells
-
The population of embryonic cells from which germ cells are formed.
- Imprinted genes
-
Genes in which one allele is expressed in a parent-of-origin-specific manner.
- Bisulphite sequencing
-
A technique in which the treatment of DNA with bisulphite, which converts cytosines into uracils but does not modify methylated cytosines, is used to determine the DNA methylation pattern.
- Vegetative nucleus
-
The nucleus of a terminally differentiated vegetative cell. It does not contribute genetic information to subsequent generations.
- Gametophyte
-
A multicellular structure that is generated from a haploid spore through mitotic cell divisions and contains the male or female gamete.
- Endosperm
-
The product of fertilization of the central cell of the female gametophyte. It is present in the seeds of most flowering plants and provides nutrition to the developing embryo.
- Primary piRNAs
-
(Primary Piwi-interacting RNAs.) The products of piRNA precursor transcript processing. These piRNAs have a preference for a 5′ uridine.
- Secondary piRNAs
-
(Secondary Piwi-interacting RNAs.) The products of a ping-pong amplification cycle. These piRNAs are antisense to primary piRNAs and have a preference for an adenine at position 10.
- Tudor domain
-
A conserved protein motif that is able to recognize symmetrically dimethylated arginines.
- Base excision repair
-
A cellular mechanism that repairs damaged DNA and is initiated by the activity of DNA glycosylases.
- Ecotype
-
A genetically distinct population within a widely spread species.
- Silique
-
An elongated seed capsule that is formed after fertilization.
- Hybrids
-
Offspring that are produced by crossing two different populations within a single species.
- Zygote
-
A single diploid cell formed by the union of two haploid germ cells.
- Blastocyst
-
An embryonic stage that is characterized by the first definitive lineages.
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Law, J., Jacobsen, S. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet 11, 204–220 (2010). https://doi.org/10.1038/nrg2719
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DOI: https://doi.org/10.1038/nrg2719
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