Unified establishment and epigenetic inheritance of DNA methylation through cooperative MET1 activity

Briffa, Amy; Hollwey, Elizabeth; Shahzad, Zaigham; Moore, Jonathan D.; Lyons, David; Howard, Martin; Zilberman, Daniel

doi:10.1101/2022.09.12.507517

Cited by 6 publications

(15 citation statements)

References 95 publications

(194 reference statements)

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“…Third, the overlap in mutated sites between the two crosses is orders of magnitude higher than could be expected under any model of random mutations. The far greater sharing along the northern lineage suggests that the same parental individual was used as mother in one direction of the cross and father in the other (this would result in sharing of half of all epimutations that occurred in the first of the two generations of the pedigree, see S13 Fig) . These observations provide further evidence (see also reference [34]) that a model of random epimutations is not sufficient, and suggest that further experiments are badly needed.…”

Section: Estimating Epimutation Ratesmentioning

confidence: 79%

“…We also see that somatic gains of methylation are positively correlated with nearby (within 30 bp) methylation, just as has been observed for trans-generational gains of methylation ( cf . Fig 6B with Fig 3 in reference [34]). It is thus reasonable to hypothesize that the QTL we identify correspond to bona fide modifiers of the epimutation rate — which makes it very interesting that they show strong G × E effects (Fig 4), as well as possible parent-of-origin effects (Fig 7).…”

Section: Discussionmentioning

confidence: 95%

“…At least two lines of evidence speak against this. First, both losses and gains are much more pronounced on sites that differ between the parental lines (Fig reference [34]).…”

Section: Discussionmentioning

confidence: 99%

“…Fig 6B with Fig 3 in reference[34]). It is thus reasonable to hypothesize that the QTL we identify correspond to bona fide modifiers of the epimutation rate -which makes it very interesting that they show strong G×E effects (Fig 4), as well as possible parent-of-origin effects (Fig7).…”

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confidence: 89%

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On the Causes of Gene-Body Methylation Variation inArabidopsis thaliana

Nizhynska

Morales

Nordborg

2022

Preprint

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Gene-body methylation (gbM) refers to sparse CG methylation of coding regions, in particular of evolutionarily conserved house-keeping genes. It is found in both plants and animals, but is directly and stably (epigenetically) inherited over multiple generations in the former. Studies inArabidopsis thalianahave demonstrated that plants originating from different parts of the world exhibit large differences in gbM, which presumably reflects an epigenetic memory of ancestral genetic and/or environmental factors. Here we look for evidence of such factors in F2 plants resulting from a cross between a southern Swedish line with low gbM and a northern Swedish line with high gbM, grown at two different temperatures. Using bisulfite-sequencing data with nucleotide-level resolution on hundreds of individuals, we confirm that CG sites are either methylated (nearly 100% methylation across sampled cells) or unmethylated (approximately 0% methylation across sampled cells), and show that the higher level of gbM in the northern line is due to more sites being methylated. Furthermore, methylation variants almost always show Mendelian segregation, consistent with their being directly and stably inherited through meiosis. To explore how the differences between the parental lines could have arisen, we focused on somatic deviations from the inherited state, distinguishing between gains (relative to the inherited 0% methylation) and losses (relative to the inherited 100% methylation) at each site in the F2 generation. We demonstrate that deviations predominantly affect sites that differ between the parental lines, consistent with these sites being more mutable. Gains and losses behave very differently in terms of the genomic distribution, and are influenced by the local chromatin state. We find clear evidence for different trans-acting genetic polymorphism affecting both gains and losses, with those affecting gains showing strong environmental interactions (G x E). Direct effects of the environment were minimal. In conclusion, we show that genetic and environmental factors can change gbM at a cellular level, and hypothesize that these factors can also lead to trans-generational differences between individuals via the inclusion of such changes in the zygote.

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Section: Estimating Epimutation Ratesmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 95%

“…At least two lines of evidence speak against this. First, both losses and gains are much more pronounced on sites that differ between the parental lines (Fig reference [34]).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 89%

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On the Causes of Gene-Body Methylation Variation inArabidopsis thaliana

Nizhynska

Morales

Nordborg

2022

Preprint

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“…De novo methylation by MET1/DNMT1 is not unprecedented – it has been observed in mammalian cells [36], and de novo CG methylation has been observed at an introduced transgene within Arabidopsis [37]. Recently, de novo CG methylation was also reported in inbred ddcc lines [38]. Heterozygous met1 mutants lose the vast majority of gene body methylation [33], including at most Dynamic GbM genes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dynamic DNA methylation turnover in gene bodies is associated with enhanced gene expression plasticity in plants

Williams

Dai

Tran

et al. 2022

Preprint

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In diverse eukaryotes, DNA methylation is deposited within the coding regions of many genes, termed gene body methylation (GbM). Whereas the role of DNA methylation on the silencing of transposons and repetitive DNA is well understood, gene body methylation is not associated with transcriptional repression, and its biological importance has remained unclear. We report a newly discovered type of GbM in plants, which is under constitutive addition and removal by dynamic methylation modifiers in all cells, including the germline. Methylation at Dynamic GbM genes is removed by the DRDD demethylation pathway, and added by an unknown source of de novo methylation, most likely the maintenance methyltransferase MET1. We show that the Dynamic GbM state is present at homologous genes across divergent lineages (>100 million years), indicating evolutionary conservation. Furthermore, we demonstrate that Dynamic GbM is tightly associated with the presence of a promoter/regulatory chromatin state within the gene body, in contrast to other gene body methylated genes. Lastly, we find Dynamic GbM is associated with enhanced gene expression plasticity across development and diverse physiological conditions, whereas stably methylated GbM genes exhibit reduced plasticity. We propose that Dynamic GbM is a hallmark of genes that can navigate a greater landscape of transcriptional states by maintaining regulatory flexibility.

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Mathematical model of RNA-directed DNA methylation predicts tuning of negative feedback required for stable maintenance

Dale,

Mosher

2024

Open Biol.

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RNA-directed DNA methylation (RdDM) is a plant-specific de novo methylation pathway that is responsible for maintenance of asymmetric methylation (CHH, H = A, T or G) in euchromatin. Loci with CHH methylation produce 24 nucleotide (nt) short interfering (si) RNAs. These siRNAs direct additional CHH methylation to the locus, maintaining methylation states through DNA replication. To understand the necessary conditions to produce stable methylation, we developed a stochastic mathematical model of RdDM. The model describes DNA target search by siRNAs derived from CHH methylated loci bound by an Argonaute. Methylation reinforcement occurs either throughout the cell cycle (steady) or immediately following replication (bursty). We compare initial and final methylation distributions to determine simulation conditions that produce stable methylation. We apply this method to the low CHH methylation case. The resulting model predicts that siRNA production must be linearly proportional to methylation levels, that bursty reinforcement is more stable and that slightly higher levels of siRNA production are required for searching DNA, compared to RNA. Unlike CG methylation, which typically exhibits bi-modality with loci having either 100% or 0% methylation, CHH methylation exists across a range. Our model predicts that careful tuning of the negative feedback in the system is required to enable stable maintenance.

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Unified establishment and epigenetic inheritance of DNA methylation through cooperative MET1 activity

Cited by 6 publications

References 95 publications

On the Causes of Gene-Body Methylation Variation inArabidopsis thaliana

On the Causes of Gene-Body Methylation Variation inArabidopsis thaliana

Dynamic DNA methylation turnover in gene bodies is associated with enhanced gene expression plasticity in plants

Mathematical model of RNA-directed DNA methylation predicts tuning of negative feedback required for stable maintenance

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