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Repression of CHROMOMETHYLASE 3 prevents epigenetic collateral damage in Arabidopsis.

ABSTRACT: DNA methylation has evolved to silence mutagenic transposable elements (TEs) while typically avoiding the targeting of endogenous genes. Mechanisms that prevent DNA methyltransferases from ectopically methylating genes are expected to be of prime importance during periods of dynamic cell cycle activities including plant embryogenesis. However, virtually nothing is known regarding how DNA methyltransferase activities are precisely regulated during embryogenesis to prevent the induction of potentially deleterious and mitotically stable genic epimutations. Here, we report that microRNA-mediated repression of CHROMOMETHYLASE 3 (CMT3) and the chromatin features that CMT3 prefers help prevent ectopic methylation of thousands of genes during embryogenesis that can persist for weeks afterwards. Our results are also consistent with CMT3-induced ectopic methylation of promoters or bodies of genes undergoing transcriptional activation reducing their expression. Therefore, the repression of CMT3 prevents epigenetic collateral damage on endogenous genes. We also provide a model that may help reconcile conflicting viewpoints regarding the functions of gene-body methylation that occurs in nearly all flowering plants.

SUBMITTER: Papareddy RK

PROVIDER: S-EPMC8352596 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Repression of CHROMOMETHYLASE 3 Prevents Epigenetic Collateral Damage in Arabidopsis

Project description:DNA methylation has evolved to silence mutagenic transposable elements (TEs) while typically avoiding the targeting of endogenous genes. Mechanisms that prevent DNA methyltransferases from ectopically methylating genes are expected to be of prime importance during periods of dynamic cell cycle activities including plant embryogenesis. However, virtually nothing is known regarding how DNA methyltransferase activities are precisely regulated during embryogenesis to prevent the induction of potentially deleterious and mitotically stable genic epimutations. Here, we report that microRNA-mediated repression of CHROMOMETHYLASE 3 (CMT3) and the chromatin features that CMT3 prefers help prevent ectopic methylation of thousands of genes during embryogenesis that can persist for weeks afterwards. Moreover, CMT3-induced ectopic methylation of genes undergoing transcriptional activation can reduce their corresponding transcript levels. Therefore, the repression of CMT3 prevents epigenetic collateral damage on endogenous genes. We also provide a model that may help reconcile conflicting viewpoints regarding the functions of gene-body methylation that occurs in nearly all flowering plants.

2021-06-01 | GSE171198 | GEO

Repression of CHROMOMETHYLASE 3 Prevents Epigenetic Collateral Damage in Arabidopsis

Project description:Repression of CHROMOMETHYLASE 3 Prevents Epigenetic Collateral Damage in Arabidopsis

| PRJNA718622 | ENA

Collateral Damage

Project description:Sequencing of two mice from a knockout mouse programme which display deafness and vestibular defects unlinked to the targeted allele.

| PRJEB45713 | ENA

Natural variation for alleles under epigenetic control by the maize chromomethylase zmet2.

Project description:The contribution of epigenetic alterations to natural variation for gene transcription levels remains unclear. In this study, we investigated the functional targets of the maize chromomethylase ZMET2 in multiple inbred lines to determine whether epigenetic changes conditioned by this chromomethylase are conserved or variable within the species. Gene expression microarrays were hybridized with RNA samples from the inbred lines B73 and Mo17 and from near-isogenic derivatives containing the loss-of-function allele zmet2-m1. A set of 126 genes that displayed statistically significant differential expression in zmet2 mutants relative to wild-type plants in at least one of the two genetic backgrounds was identified. Analysis of the transcript levels in both wild-type and mutant individuals revealed that only 10% of these genes were affected in zmet2 mutants in both B73 and Mo17 genetic backgrounds. Over 80% of the genes with expression patterns affected by zmet2 mutations display variation for gene expression between wild-type B73 and Mo17 plants. Further analysis was performed for 7 genes that were transcriptionally silent in wild-type B73, but expressed in B73 zmet2-m1, wild-type Mo17, and Mo17 zmet2-m1 lines. Mapping experiments confirmed that the expression differences in wild-type B73 relative to Mo17 inbreds for these genes were caused by cis-acting regulatory variation. Methylation-sensitive PCR and bisulfite sequencing demonstrated that for 5 of these genes the CpNpG methylation in the wild-type B73 genetic background was substantially decreased in the B73 zmet2-m1 mutant and in wild-type Mo17. A survey of eight maize inbreds reveals that each of these 5 genes exhibit transcriptionally silent and methylated states in some inbred lines and unmethylated, expressed states in other inbreds, providing evidence for natural variation in epigenetic states for some maize genes.

| S-EPMC2034640 | biostudies-literature

Ammonium Inhibits Chromomethylase 3-Mediated Methylation of the Arabidopsis Nitrate Reductase Gene NIA2.

Project description:Gene methylation is an important mechanism regulating gene expression and genome stability. Our previous work showed that methylation of the nitrate reductase (NR) gene NIA2 was dependent on chromomethylase 3 (CMT3). Here, we show that CMT3-mediated NIA2 methylation is regulated by ammonium in Arabidopsis thaliana. CHG sequences (where H can be A, T, or C) were methylated in NIA2 but not in NIA1, and ammonium [(NH4)2SO4] treatment completely blocked CHG methylation in NIA2. By contrast, ammonium had no effect on CMT3 methylation, indicating that ammonium negatively regulates CMT3-mediated NIA2 methylation without affecting CMT3 methylation. Ammonium upregulated NIA2 mRNA expression, which was consistent with the repression of NIA2 methylation by ammonium. Ammonium treatment also reduced the overall genome methylation level of wild-type Arabidopsis. Moreover, CMT3 bound to specific promoter and intragenic regions of NIA2. These combined results indicate that ammonium inhibits CMT3-mediated methylation of NIA2 and that of other target genes, and CMT3 selectively binds to target DNA sequences for methylation.

| S-EPMC4720742 | biostudies-literature

Arabidopsis cmt3 chromomethylase mutations block non-CG methylation and silencing of an endogenous gene.

Project description:Plants maintain cytosine methylation at CG and non-CG residues to control gene expression and genome stability. In a screen for Arabidopsis mutants that alter methylation and silencing of a densely methylated endogenous reporter gene, we recovered 11 loss-of-function alleles in the CMT3 chromomethylase gene. The cmt3 mutants displayed enhanced expression and reduced methylation of the reporter, particularly at non-CG cytosines. CNG methylation was also reduced at repetitive centromeric sequences. Thus, CMT3 is a key determinant for non-CG methylation. The lack of CMT homologs in animal genomes could account for the observation that in contrast to plants, animals maintain primarily CG methylation.

| S-EPMC312734 | biostudies-literature

Dominant repression by Arabidopsis transcription factor MYB44 causes oxidative damage and hypersensitivity to abiotic stress.

Project description:In any living species, stress adaptation is closely linked with major changes of the gene expression profile. As a substrate protein of the rapidly stress-induced mitogen-activated protein kinase MPK3, Arabidopsis transcription factor MYB44 likely acts at the front line of stress-induced re-programming. We recently characterized MYB44 as phosphorylation-dependent positive regulator of salt stress signaling. Molecular events downstream of MYB44 are largely unknown. Although MYB44 binds to the MBSII element in vitro, it has no discernible effect on MBSII-driven reporter gene expression in plant co-transfection assays. This may suggest limited abundance of a synergistic co-regulator. MYB44 carries a putative transcriptional repression (Ethylene responsive element binding factor-associated Amphiphilic Repression, EAR) motif. We employed a dominant repressor strategy to gain insights into MYB44-conferred stress resistance. Overexpression of a MYB44-REP fusion markedly compromised salt and drought stress tolerance--the opposite was seen in MYB44 overexpression lines. MYB44-mediated resistance likely results from induction of tolerance-enhancing, rather than from repression of tolerance-diminishing factors. Salt stress-induced accumulation of destructive reactive oxygen species is efficiently prevented in transgenic MYB44, but accelerated in MYB44-REP lines. Furthermore, heterologous overexpression of MYB44-REP caused tissue collapse in Nicotiana. A mechanistic model of MAPK-MYB-mediated enhancement in the antioxidative capacity and stress tolerance is proposed. Genetic engineering of MYB44 variants with higher trans-activating capacity may be a means to further raise stress resistance in crops.

| S-EPMC3958865 | biostudies-literature

Anticipating and Identifying Collateral Damage in Genome Editing.

Project description:Genome editing has powerful applications in research, healthcare, and agriculture. However, the range of possible molecular events resulting from genome editing has been underestimated and the technology remains unpredictable on, and away from, the target locus. This has considerable impact in providing a safe approach for therapeutic genome editing, agriculture, and other applications. This opinion article discusses how to anticipate and detect those editing events by a combination of assays to capture all possible genomic changes. It also discusses strategies for preventing unwanted effects, critical to appraise the benefit or risk associated with the use of the technology. Anticipating and verifying the result of genome editing are essential for the success for all applications.

| S-EPMC7658041 | biostudies-literature

High-Dose Vitamin C Prevents Secondary Brain Damage After Stroke via Epigenetic Reprogramming of Neuroprotective Genes.

Project description:Vitamin C has recently been identified as an epigenetic regulator by activating ten-eleven translocases (TETs), enzymes involved in generating DNA hydroxymethylcytosine (5hmC). Currently, we investigated whether high-dose vitamin C promotes neuroprotection through epigenetic modulation of 5hmC, if there are sex-specific differences in outcome, and the therapeutic potential of vitamin C in stroke-related comorbidities in adult mice. Post-stroke treatment with ascorbate (reduced form), but not dehydroascorbate (oxidized form), increased TET3 activity and 5hmC levels and reduced infarct following focal ischemia. Hydroxymethylation DNA immunoprecipitation sequencing showed that ascorbate increased 5hmC across the genome and specifically in promoters of several stroke pathophysiology-related genes, particularly anti-inflammatory genes. Ascorbate also decreased markers of oxidative stress, mitochondrial fragmentation, and apoptosis in cortical peri-infarct neurons and promoted motor and cognitive functional recovery in both sexes via TET3. Furthermore, post-stroke ascorbate treatment reduced infarct volume and improved motor function recovery in aged, hypertensive and diabetic male and female mice. Delayed ascorbate treatment at 6 h of reperfusion was still effective at reducing infarct volume and motor impairments in adult mice. Collectively, this study shows that post-stroke treatment with high-dose ascorbate protects the brain through epigenetic reprogramming and may function as a robust therapeutic against stroke injury.

| S-EPMC9485293 | biostudies-literature

BRU1, a novel link between responses to DNA damage and epigenetic gene silencing in Arabidopsis.

Project description:DNA repair associated with DNA replication is important for the conservation of genomic sequence information, whereas reconstitution of chromatin after replication sustains epigenetic information. We have isolated and characterized mutations in the BRU1 gene of Arabidopsis that suggest a novel link between these underlying maintenance mechanisms. Bru1 plants are highly sensitive to genotoxic stress and show stochastic release of transcriptional gene silencing. They also show increased intrachromosomal homologous recombination and constitutively activated expression of poly (ADP-ribose) polymerase-2 (AtPARP-2), the induction of which is associated with elevated DNA damage. Bru1 mutations affect the stability of heterochromatin organization but do not interfere with genome-wide DNA methylation. BRU1 encodes a novel nuclear protein with two predicted protein-protein interaction domains. The developmental abnormalities characteristic of bru1 mutant plants resemble those triggered by mutations in genes encoding subunits of chromatin assembly factor (CAF-1), the condensin complex, or MRE11. Comparison of bru1 with these mutants indicates cooperative roles in the replication and stabilization of chromatin structure, providing a novel link between chromatin replication, epigenetic inheritance, S-phase DNA damage checkpoints, and the regulation of meristem development.

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