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1. Recent loss of the Dim2 DNA methyltransferase decreases mutation rate in repeats and changes evolutionary trajectory in a fungal pathogen

   https://doi.org/10.1371/journal.pgen.1009448  

   Möller, Mareike; Habig, Michael; Lorrain, Cécile; Feurtey, Alice; Haueisen, Janine; Fagundes, Wagner C.; Alizadeh, Alireza; Freitag, Michael; Stukenbrock, Eva H. (March 2021, PLOS Genetics)

   Krasileva, Ksenia (Ed.)

   DNA methylation is found throughout all domains of life, yet the extent and function of DNA methylation differ among eukaryotes. Strains of the plant pathogenic fungus Zymoseptoria tritici appeared to lack cytosine DNA methylation (5mC) because gene amplification followed by Repeat-Induced Point mutation (RIP) resulted in the inactivation of the dim2 DNA methyltransferase gene. 5mC is, however, present in closely related sister species. We demonstrate that inactivation of dim2 occurred recently as some Z . tritici isolates carry a functional dim2 gene. Moreover, we show that dim2 inactivation occurred by a different path than previously hypothesized. We mapped the genome-wide distribution of 5mC in strains with or without functional dim2 alleles. Presence of functional dim2 correlates with high levels of 5mC in transposable elements (TEs), suggesting a role in genome defense. We identified low levels of 5mC in strains carrying non-functional dim2 alleles, suggesting that 5mC is maintained over time, presumably by an active Dnmt5 DNA methyltransferase. Integration of a functional dim2 allele in strains with mutated dim2 restored normal 5mC levels, demonstrating de novo cytosine methylation activity of Dim2. To assess the importance of 5mC for genome evolution, we performed an evolution experiment, comparing genomes of strains with high levels of 5mC to genomes of strains lacking functional dim2 . We found that presence of a functional dim2 allele alters nucleotide composition by promoting C to T transitions (C→T) specifically at CpA (CA) sites during mitosis, likely contributing to TE inactivation. Our results show that 5mC density at TEs is a polymorphic trait in Z . tritici populations that can impact genome evolution. 

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2. Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

   https://doi.org/10.1038/s41467-025-56928-1  

   Palczewski, Marianne B; Kuschman, Hannah Petraitis; Hoffman, Brian M; Kathiresan, Venkatesan; Yang, Hao; Glynn, Sharon A; Wilson, David L; Kool, Eric T; Montfort, William R; Chang, Jenny; et al (February 2025, Nature Communications)

   Abstract DNA methylation at cytosine bases (5-methylcytosine, 5mC) is a heritable epigenetic mark regulating gene expression. While enzymes that metabolize 5mC are well-characterized, endogenous signaling molecules that regulate DNA methylation machinery have not been described. We report that physiological nitric oxide (NO) concentrations reversibly inhibit the DNA demethylases TET and ALKBH2 by binding to the mononuclear non-heme iron atom forming a dinitrosyliron complex (DNIC) and preventing cosubstrates from binding. In cancer cells treated with exogenous NO, or endogenously synthesizing NO, 5mC and 5-hydroxymethylcytosine (5hmC) increase, with no changes in DNA methyltransferase activity. 5mC is also significantly increased in NO-producing patient-derived xenograft tumors from mice. Genome-wide methylome analysis of cells chronically treated with NO (10 days) shows enrichment of 5mC and 5hmC at gene-regulatory loci, correlating with altered expression of NO-regulated tumor-associated genes. Regulation of DNA methylation is distinctly different from canonical NO signaling and represents a unique epigenetic role for NO. 

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3. Evolution of DNA methylation in the human brain

   https://doi.org/10.1038/s41467-021-21917-7  

   Jeong, Hyeonsoo; Mendizabal, Isabel; Berto, Stefano; Chatterjee, Paramita; Layman, Thomas; Usui, Noriyoshi; Toriumi, Kazuya; Douglas, Connor; Singh, Devika; Huh, Iksoo; et al (December 2021, Nature Communications)

   null (Ed.)

   Abstract DNA methylation is a critical regulatory mechanism implicated in development, learning, memory, and disease in the human brain. Here we have elucidated DNA methylation changes during recent human brain evolution. We demonstrate dynamic evolutionary trajectories of DNA methylation in cell-type and cytosine-context specific manner. Specifically, DNA methylation in non-CG context, namely CH methylation, has increased (hypermethylation) in neuronal gene bodies during human brain evolution, contributing to human-specific down-regulation of genes and co-expression modules. The effects of CH hypermethylation is particularly pronounced in early development and neuronal subtypes. In contrast, DNA methylation in CG context shows pronounced reduction (hypomethylation) in human brains, notably in cis-regulatory regions, leading to upregulation of downstream genes. We show that the majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and harbors strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage since the divergence from the chimpanzee lineage and carries significant genetic risk for schizophrenia. Therefore, recent epigenetic evolution of human cortex has shaped the cellular regulatory landscape and contributed to the increased vulnerability to neuropsychiatric diseases. 

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4. Not all Is SET for Methylation: Evolution of Eukaryotic Protein Methyltransferases

   https://doi.org/10.1007/978-1-0716-2481-4_1  

   Erlendson AA; Freitag M (June 2022, Methods in molecular biology)

   Margueron R; Holoch D (Ed.)

   Dynamic posttranslational modifications to canonical histones that constitute the nucleosome (H2A, H2B, H3, and H4) control all aspects of enzymatic transactions with DNA. Histone methylation has been studied heavily for the past 20 years, and our mechanistic understanding of the control and function of individual methylation events on specific histone arginine and lysine residues has been greatly improved over the past decade, driven by excellent new tools and methods. Here, we will summarize what is known about the distribution and some of the functions of protein methyltransferases from all major eukaryotic supergroups. The main conclusion is that protein, and specifically histone, methylation is an ancient process. Many taxa in all supergroups have lost some subfamilies of both protein arginine methyltransferases (PRMT) and the heavily studied SET domain lysine methyltransferases (KMT). Over time, novel subfamilies, especially of SET domain proteins, arose. We use the interactions between H3K27 and H3K36 methylation as one example for the complex circuitry of histone modifications that make up the “histone code,” and we discuss one recent example (Paramecium Ezl1) for how extant enzymes that may resemble more ancient SET domain KMTs are able to modify two lysine residues that have divergent functions in plants, fungi, and animals. Complexity of SET domain KMT function in the well-studied plant and animal lineages arose not only by gene duplication but also acquisition of novel DNA- and histone-binding domains in certain subfamilies. 

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5. The role of Dmnt1 during spermatogenesis of the insect Oncopeltus fasciatus

   https://doi.org/10.1186/s13072-023-00496-5  

   Cunningham, Christopher B.; Shelby, Emily A.; McKinney, Elizabeth C.; Schmitz, Robert J.; Moore, Allen J.; Moore, Patricia J. (December 2023, Epigenetics & Chromatin)

   Abstract Background The function of DNA methyltransferase genes of insects is a puzzle, because an association between gene expression and methylation is not universal for insects. If the genes normally involved in cytosine methylation are not influencing gene expression, what might be their role? We previously demonstrated that gametogenesis of Oncopeltus fasciatus is interrupted at meiosis following knockdown of DNA methyltransferase 1 ( Dnmt1 ) and this is unrelated to changes in levels of cytosine methylation. Here, using transcriptomics, we tested the hypothesis that Dmnt1 is a part of the meiotic gene pathway. Testes, which almost exclusively contain gametes at varying stages of development, were sampled at 7 days and 14 days following knockdown of Dmnt1 using RNAi. Results Using microscopy, we found actively dividing spermatocysts were reduced at both timepoints. However, as with other studies, we saw Dnmt1 knockdown resulted in condensed nuclei after mitosis–meiosis transition, and then cellular arrest. We found limited support for a functional role for Dnmt1 in our predicted cell cycle and meiotic pathways. An examination of a priori Gene Ontology terms showed no enrichment for meiosis. We then used the full data set to reveal further candidate pathways influenced by Dnmt1 for further hypotheses. Very few genes were differentially expressed at 7 days, but nearly half of all transcribed genes were differentially expressed at 14 days. We found no strong candidate pathways for how Dnmt1 knockdown was achieving its effect through Gene Ontology term overrepresentation analysis. Conclusions We, therefore, suggest that Dmnt1 plays a role in chromosome dynamics based on our observations of condensed nuclei and cellular arrest with no specific molecular pathways disrupted. 

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