Evolutionary analysis indicates that DNA alkylation damage is a byproduct of cytosine DNA methyltransferase activity

Rošić, Silvana; Amouroux, Rachel; Requena, Cristina E.; Gomes, Ana; Emperle, Max; Beltran, Toni; Rane, Jayant K.; Linnett, Sarah; Selkirk, Murray E.; Schiffer, Philipp H.; Bancroft, Allison J.; Grencis, Richard K.; Jeltsch, Albert; Hájková, Petra; Sarkies, Peter

doi:10.1038/s41588-018-0061-8

Cited by 79 publications

(88 citation statements)

References 35 publications

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“…The distribution of 5mC across genomes is tied to the evolution of DNA methyltransferase (DNMT) enzymes, whose genes have undergone duplication and/or loss since the last common eukaryotic ancestor 47 . The dynamic nature of Dnmt gene evolution is particularly notable in the nematode lineage, where relatively closely related species display different numbers of Dnmt genes, including species where these genes are altogether absent, such as in C. elegans 49 . Interestingly, Dnmt-containing nematodes display an enrichment of 5mC at TEs, further suggesting a link between the emergence of 5mC and TE silencing 49 .…”

Section: [H1] Introductionmentioning

confidence: 99%

Regulation of transposable elements by DNA modifications

2019

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Maintenance of genome stability requires control over the expression of transposable elements (TEs), whose activity can have substantial deleterious effects on the host. Chemical modification of DNA is a commonly used strategy to achieve this, and it has long been argued that the emergence of 5-methylcytosine (5mC) in many species was driven by the requirement to silence TEs. Potential roles in TE regulation have also been suggested for other DNA modifications, such as N6-methyladenine and oxidation derivatives of 5mC, although the underlying mechanistic relationships are poorly understood. Here, we discuss current evidence implicating DNA modifications and DNA modifying enzymes in TE regulation across different species. 100 LINE-1 elements account for virtually all of the transposition activity observed today 18 , including retrotransposition of non-autonomous short interspersed nuclear elements (SINEs), which depend on proteins encoded by LINE-1 elements 19. Although many TEs are neutral in their effect on the host, some insertions can disrupt gene function or lead to harmful chromosomal rearrangements, as demonstrated by over 120 disease-causing TE insertions in humans 20. Additionally, exacerbated TE expression in the germline can lead to sterility in mice and fruit flies 21,22. The resulting selective pressure has driven the evolution of numerous transcriptional and posttranscriptional host defence mechanisms that repress TE expression (Figure 2), which have been recently reviewed by Molaro and Malik 22. Small RNAs, including PIWI-interacting RNAs [G] (piRNAs), are the

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Section: [H1] Introductionmentioning

confidence: 99%

Regulation of transposable elements by DNA modifications

2019

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“…DNMT3 was absent from the genomes of 14 species, with inspection of the tree suggesting at least eight independent losses (Figure 1C). Several of these species possessed moderate levels of CpG methylation (Figure 1B), indicating that DNMT1 alone can be sufficient for introducing genome-wide DNA methylation, consistent with earlier studies in arthropods and nematodes (Xiang et al ., 2010; Bewick et al ., 2017; Rošić et al ., 2018).…”

Section: Resultsmentioning

confidence: 99%

“…Across the eukaryotes ALKB2, which repairs DNA alkylation damage introduced by DNMTs, tends to be lost from the same taxa as DNMT1 and 3 (Rošić et al ., 2018). Arthropods exhibited many exceptions to this general rule—there have been at least five losses of ALKB2 but only one of these is associated with the loss of DNMT1 and 3 (Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

Widespread conservation and lineage-specific diversification of genome-wide DNA methylation patterns across arthropods

Lewis

Ross²,

Bain³

et al. 2020

Preprint

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Cytosine methylation is an ancient epigenetic modification yet its function and extent within genomes is highly variable across eukaryotes. In mammals, methylation controls transposable elements and regulates the promoters of genes. In insects, DNA methylation is generally restricted to a small subset of transcribed genes, with both intergenic regions and transposable elements (TEs) depleted of methylation. The evolutionary origin and the function of these methylation patterns are poorly understood. Here we characterise the evolution of DNA methylation across the arthropod phylum. While the common ancestor of the arthropods had low levels of TE methylation and did not methylate promoters, both of these functions have evolved independently in centipedes and mealybugs. In contrast, methylation of the exons of a subset of transcribed genes is ancestral and widely conserved across the phylum, but has been lost in specific lineages. Remarkably the same set of genes are likely to be methylated in all species that retained exon-enriched methylation. We show that these genes have characteristic patterns of expression correlating to broad transcription initiation sites and well-positioned nucleosomes, providing new insights into potential mechanisms driving methylation patterns over hundreds of millions of years.Author SummaryAnimals develop from a single cell to form a complex organism with many specialised cells. Almost all of the fantastic variety of cells must have the same sequence of DNA, and yet they have distinct identities that are preserved even when they divide. This remarkable process is achieved by turning different sets of genes on or off in different types of cell using molecular mechanisms known as “epigenetic gene regulation”.Surprisingly, though all animals need epigenetic gene regulation, there is a huge diversity in the mechanisms that they use. Characterising and explaining this diversity is crucial in understanding the functions of epigenetic pathways, many of which have key roles in human disease. We studied how one particular type of epigenetic regulation, known as DNA methylation, has evolved within arthropods. Arthropods are an extraordinarily diverse group of animals ranging from horseshoe crabs to fruit flies. We discovered that the levels of DNA methylation and where it is found within the genome changes rapidly throughout arthropod evolution. Nevertheless, there are some features of DNA methylation that seem to be the same across most arthropods-in particular we found that there is a tendency for a similar set of genes to acquire methylation of DNA in most arthropods, and that this is conserved over 350 million years. We discovered that these genes have distinct features that might explain how methylation gets targeted. Our work provides important new insights into the evolution of DNA methylation and gives some new hints to its essential functions.

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“…Thus suggesting potential role of aberrantly methylated bases in regulation of gene expression. This is particularly interesting in light of recent work that indicated coevolution of epigenetic DNA methylation with repair of aberrantly methylated DNA bases, including AAG-initiated BER 38 . Increased level of aberrantly methylated AAG substrates at the 3'end of co-regulated genes (Supplementary figure 6) could directly be cause by RNA pol II accumulation, which indicative of a reduced elongation rate due to increased nucleosome density 39 .…”

Section: Discussionmentioning

confidence: 99%

“Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression”

Montaldo¹,

Bordin²,

Brambilla³

et al. 2019

Preprint

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Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG; aka MPG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here we show that AAG binds to chromatin and forms complex with active RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation.Importantly, at co-regulated genes aberrantly methylated bases accumulate towards 3'end, in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide novel insights to maintaining genome stability in actively transcribing chromatin, and reveal roles of aberrantly methylated bases in regulation of gene expression.

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Evolutionary analysis indicates that DNA alkylation damage is a byproduct of cytosine DNA methyltransferase activity

Cited by 79 publications

References 35 publications

Regulation of transposable elements by DNA modifications

Regulation of transposable elements by DNA modifications

Widespread conservation and lineage-specific diversification of genome-wide DNA methylation patterns across arthropods

“Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression”

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