Evolution of DNA methylation across Ecdysozoa

DNA methylation is a crucial, abundant mechanism of gene regulation in vertebrates. It is less prevalent in many other metazoan organisms and completely absent in some key model species, such as D. melanogaster and C. elegans. We report here a comprehensive study of the presence and absence of DNA methyltransferases (DNMTs) in 138 Ecdysozoa, covering Arthropoda, Nematoda, Priapulida, Onychophora, and Tardigrada. Three of these phyla have not been investigated for the presence of DNA methylation before. We observe that the loss of individual DNMTs independently occurred multiple times across ecdysozoan phyla. We computationally predict the presence of DNA methylation based on CpG rates in coding sequences using an implementation of Gaussian Mixture Modelling, MethMod. Integrating both analysis we predict two previously unknown losses of DNA methylation in Ecdysozoa, one within Chelicerata (Mesostigmata) and one in Tardigrada. In the early-branching Ecdysozoa Priapulus caudatus we predict the presence of a full set of DNMTs and the presence of DNA methylation. We are therefore showing a very diverse and independent evolution of DNA methylation in different ecdysozoan phyla spanning a phylogenetic range of more than 700 million years.

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DNA Methylation in Cancer and Development: An Evolving Paradigm

Blood ◽

10.1182/blood.v130.suppl_1.sci-50.sci-50 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. SCI-50-SCI-50

Author(s):

Maria E. Figueroa

Keyword(s):

Dna Methylation ◽

Gene Regulation ◽

Cytosine Methylation ◽

Conflicts Of Interest ◽

Cpg Islands ◽

Dna Methyltransferases ◽

Dna Demethylation ◽

Epigenetic Mark ◽

Cpg Dinucleotides ◽

Promoter Dna

DNA methylation is an epigenetic mark which, in mammals, occurs primarily on position 5 of cytosines, especially at those found in the context of CpG dinucleotides. This CpG methylation is known to play a major role in gene regulation. Cytosine methylation is regulated by the DNA methyltransferases, responsible for adding the methyl group to unmethylated CpGs, and the TET dioxygenases, involved in the DNA demethylation pathway. Initially, DNA methylation was believed to be important mainly for gene silencing through promoter DNA methylation, especially at CpG-rich promoters containing CpG islands. However, our understanding of the role that DNA methylation plays in gene regulation during normal development and how this process becomes deregulated in cancer, has evolved in recent years. Moreover, the discovery of frequent mutations in DNMT3A and TET2 both in clonal hematopoiesis of indeterminate significance as well as in many hematological malignancies has brought new interest into understanding what role DNA methylation plays in normal HSC function as well as how it contributes to malignant transformation. In this session, we will review the current understanding in the field of DNA methylation and gene regulation, and present data on DNA methylation in normal HSCs as well as the role that this epigenetic mark plays during leukemic transformation in acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

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Neuroblastoma and the epigenome

Cancer and Metastasis Reviews ◽

10.1007/s10555-020-09946-y ◽

2021 ◽

Author(s):

Irfete S. Fetahu ◽

Sabine Taschner-Mandl

Keyword(s):

Dna Methylation ◽

Histone Modifications ◽

Disease Diagnosis ◽

Dna Methyltransferases ◽

Epigenetic Alterations ◽

Aberrant Expression ◽

Tet Proteins ◽

Relative Paucity ◽

Underlying Causes ◽

Aberrant Dna Methylation

AbstractNeuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system and one of the most common solid tumors in infancy. Amplification of MYCN, copy number alterations, numerical and segmental chromosomal aberrations, mutations, and rearrangements on a handful of genes, such as ALK, ATRX, TP53, RAS/MAPK pathway genes, and TERT, are attributed as underlying causes that give rise to NB. However, the heterogeneous nature of the disease—along with the relative paucity of recurrent somatic mutations—reinforces the need to understand the interplay of genetic factors and epigenetic alterations in the context of NB. Epigenetic mechanisms tightly control gene expression, embryogenesis, imprinting, chromosomal stability, and tumorigenesis, thereby playing a pivotal role in physio- and pathological settings. The main epigenetic alterations include aberrant DNA methylation, disrupted patterns of posttranslational histone modifications, alterations in chromatin composition and/or architecture, and aberrant expression of non-coding RNAs. DNA methylation and demethylation are mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, respectively, while histone modifications are coordinated by histone acetyltransferases and deacetylases (HATs, HDACs), and histone methyltransferases and demethylases (HMTs, HDMs). This article focuses predominately on the crosstalk between the epigenome and NB, and the implications it has on disease diagnosis and treatment.

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Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms22073735 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3735

Author(s):

Guillaume Velasco ◽

Damien Ulveling ◽

Sophie Rondeau ◽

Pauline Marzin ◽

Motoko Unoki ◽

...

Keyword(s):

Dna Methylation ◽

Catalytic Domain ◽

De Novo ◽

Mutation Screening ◽

Histone H3 ◽

Regulatory Elements ◽

Germline Mutations ◽

Dna Methyltransferases ◽

Mendelian Disorders ◽

Epigenetic Machinery

DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.

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Arabidopsis MORC proteins function in the efficient establishment of RNA directed DNA methylation

Nature Communications ◽

10.1038/s41467-021-24553-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yan Xue ◽

Zhenhui Zhong ◽

C. Jake Harris ◽

Javier Gallego-Bartolomé ◽

Ming Wang ◽

...

Keyword(s):

Dna Methylation ◽

Arabidopsis Thaliana ◽

Transposable Element ◽

Zinc Finger ◽

Protein Function ◽

C Elegans ◽

Eukaryotic Organisms

AbstractThe Microrchidia (MORC) family of ATPases are required for transposable element (TE) silencing and heterochromatin condensation in plants and animals, and C. elegans MORC-1 has been shown to topologically entrap and condense DNA. In Arabidopsis thaliana, mutation of MORCs has been shown to reactivate silent methylated genes and transposons and to decondense heterochromatic chromocenters, despite only minor changes in the maintenance of DNA methylation. Here we provide the first evidence localizing Arabidopsis MORC proteins to specific regions of chromatin and find that MORC4 and MORC7 are closely co-localized with sites of RNA-directed DNA methylation (RdDM). We further show that MORC7, when tethered to DNA by an artificial zinc finger, can facilitate the establishment of RdDM. Finally, we show that MORCs are required for the efficient RdDM mediated establishment of DNA methylation and silencing of a newly integrated FWA transgene, even though morc mutations have no effect on the maintenance of preexisting methylation at the endogenous FWA gene. We propose that MORCs function as a molecular tether in RdDM complexes to reinforce RdDM activity for methylation establishment. These findings have implications for MORC protein function in a variety of other eukaryotic organisms.

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Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies

Scientific Reports ◽

10.1038/s41598-021-82714-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cristian Carmeli ◽

Zoltán Kutalik ◽

Pashupati P. Mishra ◽

Eleonora Porcu ◽

Cyrille Delpierre ◽

...

Keyword(s):

Dna Methylation ◽

Gene Regulation ◽

Cohort Studies ◽

Early Life ◽

Life Experiences ◽

Socioeconomic Disadvantage ◽

Mediating Role ◽

The Impact ◽

The Relationship

AbstractIndividuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.

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DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors

Cerebral Cortex ◽

10.1093/cercor/bhaa337 ◽

2020 ◽

Author(s):

Jing Wei ◽

Jia Cheng ◽

Nicholas J Waddell ◽

Zi-Jun Wang ◽

Xiaodong Pang ◽

...

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

Epigenetic Modification ◽

Substantial Reduction ◽

Dna Methyltransferases ◽

Male Rats ◽

Neural Pathways ◽

Dnmt Inhibitors ◽

Synaptic Functions

Abstract Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.

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Impact of DNA methylation on 3D genome structure

Nature Communications ◽

10.1038/s41467-021-23142-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Diana Buitrago ◽

Mireia Labrador ◽

Juan Pablo Arcon ◽

Rafael Lema ◽

Oscar Flores ◽

...

Keyword(s):

Dna Methylation ◽

Chromatin Structure ◽

Chromatin Condensation ◽

Genome Structure ◽

Dna Methyltransferases ◽

Model System ◽

Structure And Function ◽

3D Genome ◽

Cellular Machinery ◽

And Function

AbstractDetermining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases in Saccharomyces cerevisiae and analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5’ end of the gene increasing gradually toward the 3’ end, with concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites respectively, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.

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Decreased expression of DNA methyltransferases in the testes of patients with non-obstructive azoospermia leads to changes in global DNA methylation levels

Reproduction Fertility and Development ◽

10.1071/rd18246 ◽

2019 ◽

Vol 31 (8) ◽

pp. 1386 ◽

Cited By ~ 1

Author(s):

Fatma Uysal ◽

Gokhan Akkoyunlu ◽

Saffet Ozturk

Keyword(s):

Dna Methylation ◽

Male Infertility ◽

De Novo ◽

Biological Effects ◽

Testicular Biopsy ◽

Round Spermatid ◽

Dna Methyltransferases ◽

Global Dna Methylation ◽

Obstructive Azoospermia ◽

Spermatogenic Cells

DNA methylation plays key roles in epigenetic regulation during mammalian spermatogenesis. DNA methyltransferases (DNMTs) function in de novo and maintenance methylation processes by adding a methyl group to the fifth carbon atom of the cytosine residues within cytosine–phosphate–guanine (CpG) and non-CpG dinucleotide sites. Azoospermia is one of the main causes of male infertility, and is classified as obstructive (OA) or non-obstructive (NOA) azoospermia based on histopathological characteristics. The molecular background of NOA is still largely unknown. DNA methylation performed by DNMTs is implicated in the transcriptional regulation of spermatogenesis-related genes. The aim of the present study was to evaluate the cellular localisation and expression levels of the DNMT1, DNMT3A and DNMT3B proteins, as well as global DNA methylation profiles in testicular biopsy samples obtained from men with various types of NOA, including hypospermatogenesis (hyposperm), round spermatid (RS) arrest, spermatocyte (SC) arrest and Sertoli cell-only (SCO) syndrome. In the testicular biopsy samples, DNMT1 expression and global DNA methylation levels decreased gradually from the hyposperm to SCO groups (P<0.05). DNMT3A expression was significantly decreased in the RS arrest, SC arrest and SCO groups compared with the hyposperm group (P<0.05). DNMT3B expression was significantly lower in the RS arrest and SCO groups than in the hyposperm group (P<0.05). Although both DNMT1 and DNMT3A were localised in the cytoplasm and nucleus of the spermatogenic cells, staining for DNMT3B was more intensive in the nucleus of spermatogenic cells. In conclusion, the findings suggest that significant changes in DNMT expression and global DNA methylation levels in spermatogenic cells may contribute to development of male infertility in the NOA groups. Further studies are needed to determine the molecular biological effects of the altered DNMT expression and DNA methylation levels on development of male infertility.

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On the origin and evolutionary consequences of gene body DNA methylation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1604666113 ◽

2016 ◽

Vol 113 (32) ◽

pp. 9111-9116 ◽

Cited By ~ 149

Author(s):

Adam J. Bewick ◽

Lexiang Ji ◽

Chad E. Niederhuth ◽

Eva-Maria Willing ◽

Brigitte T. Hofmeister ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Recombinant Inbred Lines ◽

Dna Methyltransferases ◽

Inbred Lines ◽

Gene Body ◽

Gene Body Methylation ◽

Eutrema Salsugineum ◽

And Function ◽

Evolutionary Consequences

In plants, CG DNA methylation is prevalent in the transcribed regions of many constitutively expressed genes (gene body methylation; gbM), but the origin and function of gbM remain unknown. Here we report the discovery that Eutrema salsugineum has lost gbM from its genome, to our knowledge the first instance for an angiosperm. Of all known DNA methyltransferases, only CHROMOMETHYLASE 3 (CMT3) is missing from E. salsugineum. Identification of an additional angiosperm, Conringia planisiliqua, which independently lost CMT3 and gbM, supports that CMT3 is required for the establishment of gbM. Detailed analyses of gene expression, the histone variant H2A.Z, and various histone modifications in E. salsugineum and in Arabidopsis thaliana epigenetic recombinant inbred lines found no evidence in support of any role for gbM in regulating transcription or affecting the composition and modification of chromatin over evolutionary timescales.

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