scholarly journals Substrate deformation regulates DRM2-mediated DNA methylation in plants

2021 ◽  
Vol 7 (23) ◽  
pp. eabd9224
Author(s):  
Jian Fang ◽  
Sarah M. Leichter ◽  
Jianjun Jiang ◽  
Mahamaya Biswal ◽  
Jiuwei Lu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Substrate Specificity ◽  
Genome Stability ◽  
Underlying Mechanism ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanism ◽  
Shape Complementarity ◽  
Dna Deformation ◽  
Catalytic Loop ◽  
Arginine Finger

DNA methylation is a major epigenetic mechanism critical for gene expression and genome stability. In plants, domains rearranged methyltransferase 2 (DRM2) preferentially mediates CHH (H = C, T, or A) methylation, a substrate specificity distinct from that of mammalian DNA methyltransferases. However, the underlying mechanism is unknown. Here, we report structure-function characterization of DRM2-mediated methylation. An arginine finger from the catalytic loop intercalates into the nontarget strand of DNA through the minor groove, inducing large DNA deformation that affects the substrate preference of DRM2. The target recognition domain stabilizes the enlarged major groove via shape complementarity rather than base-specific interactions, permitting substrate diversity. The engineered DRM2 C397R mutation introduces base-specific contacts with the +2-flanking guanine, thereby shifting the substrate specificity of DRM2 toward CHG DNA. Together, this study uncovers DNA deformation as a mechanism in regulating the specificity of DRM2 toward diverse CHH substrates and illustrates methylome complexity in plants.

scholarly journals Substrate deformation regulates DRM2-mediated DNA methylation in plants

2020 ◽  
Author(s):  
Jian Fang ◽  
Sarah M. Leichter ◽  
Jianjun Jiang ◽  
Mahamaya Biswal ◽  
Jiuwei Lu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Substrate Specificity ◽  
Underlying Mechanism ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanism ◽  
Dna Minor Groove ◽  
Shape Complementarity ◽  
Dna Deformation ◽  
Catalytic Loop ◽  
Arginine Finger

AbstractDNA methylation is an important epigenetic mechanism that critically regulates gene expression and genomic stability. In plants, Domains Rearranged Methyltransferase 2 (DRM2) preferentially mediates CHH methylation (H=C, T, A), a substrate specificity distinct from that of mammalian DNA methyltransferases. However, the underlying mechanism is unknown. Here, we report structure-function characterizations of DRM2-mediated methylation. An arginine finger from the catalytic loop intercalates into DNA minor groove, inducing large DNA deformation that impacts the substrate specificity of DRM2. To accommodate the substrate deformation, the target recognition domain of DRM2 embraces the enlarged DNA major groove via shape complementarity, disruption of which via C397R mutation shifts the substrate specificity of DRM2 toward CHG DNA. This study uncovers DNA deformation as a mechanism in regulating the substrate specificity of DRM2, implicative of transposon-specific repression in plants.

scholarly journals Evolutionary History of DNA Methylation Related Genes in Bivalvia: New Insights From Mytilus galloprovincialis

2021 ◽  
Vol 9 ◽  
Author(s):  
Marco Gerdol ◽  
Claudia La Vecchia ◽  
Maria Strazzullo ◽  
Pasquale De Luca ◽  
Stefania Gorbi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Mytilus Galloprovincialis ◽  
Adult Life ◽  
Dna Methyltransferases ◽  
Methylation Pattern ◽  
Epigenetic Mechanism ◽  
Specific Gene ◽  
Fundamental Information ◽  
Genome Activity

DNA methylation is an essential epigenetic mechanism influencing gene expression in all organisms. In metazoans, the pattern of DNA methylation changes during embryogenesis and adult life. Consequently, differentiated cells develop a stable and unique DNA methylation pattern that finely regulates mRNA transcription during development and determines tissue-specific gene expression. Currently, DNA methylation remains poorly investigated in mollusks and completely unexplored in Mytilus galloprovincialis. To shed light on this process in this ecologically and economically important bivalve, we screened its genome, detecting sequences homologous to DNA methyltransferases (DNMTs), methyl-CpG-binding domain (MBD) proteins and Ten-eleven translocation methylcytosine dioxygenase (TET) previously described in other organisms. We characterized the gene architecture and protein domains of the mussel sequences and studied their phylogenetic relationships with the ortholog sequences from other bivalve species. We then comparatively investigated their expression levels across different adult tissues in mussel and other bivalves, using previously published transcriptome datasets. This study provides the first insights on DNA methylation regulators in M. galloprovincialis, which may provide fundamental information to better understand the complex role played by this mechanism in regulating genome activity in bivalves.

scholarly journals Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms

2020 ◽  
Author(s):  
Linfeng Gao ◽  
Max Emperle ◽  
Yiran Guo ◽  
Sara A Grimm ◽  
Wendan Ren ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Target Selection ◽  
Dna Methyltransferases ◽  
Recognition Mechanism ◽  
Layered Substrate ◽  
Structural Enzymology ◽  
Catalytic Loop ◽  
Methylation Patterns

AbstractMammalian DNA methylation patterns are established by two de novo DNA methyltransferases DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals crucial and distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.

scholarly journals Repression of TERRA Expression by Subtelomeric DNA Methylation Is Dependent on NRF1 Binding

2019 ◽  
Vol 20 (11) ◽  
pp. 2791 ◽  
Author(s):  
Gabriel Le Berre ◽  
Virginie Hossard ◽  
Jean-Francois Riou ◽  
Anne-Laure Guieysse-Peugeot
Keyword(s):  
Dna Methylation ◽  
Cpg Islands ◽  
Underlying Mechanism ◽  
Human Cell Line ◽  
Dna Methyltransferases ◽  
Fine Tuning ◽  
Experimental Conditions ◽  
Nuclear Respiratory Factor ◽  
Compound C ◽  
Cell Line Hela

Chromosome ends are transcribed into long noncoding telomeric repeat-containing RNA (TERRA) from subtelomeric promoters. A class of TERRA promoters are associated with CpG islands embedded in repetitive DNA tracts. Cytosines in these subtelomeric CpG islands are frequently methylated in telomerase-positive cancer cells, and demethylation induced by depletion of DNA methyltransferases is associated with increased TERRA levels. However, the direct evidence and the underlying mechanism regulating TERRA expression through subtelomeric CpG islands methylation are still to establish. To analyze TERRA regulation by subtelomeric DNA methylation in human cell line (HeLa), we used an epigenetic engineering tool based on CRISPR-dCas9 (clustered regularly interspaced short palindromic repeats – dead CRISPR associated protein 9) associated with TET1 (ten-eleven 1 hydroxylase) to specifically demethylate subtelomeric CpG islands. This targeted demethylation caused an up-regulation of TERRA, and the enhanced TERRA production depended on the methyl-sensitive transcription factor NRF1 (nuclear respiratory factor 1). Since AMPK (AMP-activated protein kinase) is a well-known activator of NRF1, we treated cells with an AMPK inhibitor (compound C). Surprisingly, compound C treatment increased TERRA levels but did not inhibit AMPK activity in these experimental conditions. Altogether, our results provide new insight in the fine-tuning of TERRA at specific subtelomeric promoters and could allow identifying new regulators of TERRA.

scholarly journals DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes

2020 ◽  
Vol 21 (15) ◽  
pp. 5420
Author(s):  
Cathrin Bayer ◽  
Georg Pitschelatow ◽  
Nina Hannemann ◽  
Jenice Linde ◽  
Julia Reichard ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Neurodegenerative Diseases ◽  
Dna Methyltransferase ◽  
Underlying Mechanism ◽  
Dna Methyltransferases ◽  
Term Survival ◽  
Expression Studies ◽  
Autophagy Pathway ◽  
Biochemical Analyses

The limited regenerative capacity of neurons requires a tightly orchestrated cell death and survival regulation in the context of longevity, as well as age-associated and neurodegenerative diseases. Subordinate to genetic networks, epigenetic mechanisms, such as DNA methylation and histone modifications, are involved in the regulation of neuronal functionality and emerge as key contributors to the pathophysiology of neurodegenerative diseases. DNA methylation, a dynamic and reversible process, is executed by DNA methyltransferases (DNMTs). DNMT1 was previously shown to act on neuronal survival in the aged brain, whereby a DNMT1-dependent modulation of processes relevant for protein degradation was proposed as an underlying mechanism. Properly operating proteostasis networks are a mandatory prerequisite for the functionality and long-term survival of neurons. Malfunctioning proteostasis is found, inter alia, in neurodegenerative contexts. Here, we investigated whether DNMT1 affects critical aspects of the proteostasis network by a combination of expression studies, live cell imaging, and protein biochemical analyses. We found that DNMT1 negatively impacts retrograde trafficking and autophagy, with both being involved in the clearance of aggregation-prone proteins by the aggresome–autophagy pathway. In line with this, we found that the transport of GFP-labeled mutant huntingtin (HTT) to perinuclear regions, proposed to be cytoprotective, also depends on DNMT1. Depletion of Dnmt1 accelerated perinuclear HTT aggregation and improved the survival of cells transfected with mutant HTT. This suggests that mutant HTT-induced cytotoxicity is at least in part mediated by DNMT1-dependent modulation of degradative pathways.

scholarly journals Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration

2018 ◽  
Vol 115 (52) ◽  
pp. E12417-E12426 ◽  
Author(s):  
Young Mi Oh ◽  
Marcus Mahar ◽  
Eric E. Ewan ◽  
Kathleen M. Leahy ◽  
Guoyan Zhao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
Axon Regeneration ◽  
Ring Finger ◽  
Suppressor Gene ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanism ◽  
Nerve Lesion ◽  
Axon Injury ◽  
Epigenetic Regulator

Injured peripheral sensory neurons switch to a regenerative state after axon injury, which requires transcriptional and epigenetic changes. However, the roles and mechanisms of gene inactivation after injury are poorly understood. Here, we show that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. Ubiquitin-like containing PHD ring finger 1 (UHRF1), a critical epigenetic regulator involved in DNA methylation, increases upon axon injury and is required for robust axon regeneration. The increased level of UHRF1 results from a decrease in miR-9. The level of another target of miR-9, the transcriptional regulator RE1 silencing transcription factor (REST), transiently increases after injury and is required for axon regeneration. Mechanistically, UHRF1 interacts with DNA methyltransferases (DNMTs) and H3K9me3 at the promoter region to repress the expression of the tumor suppressor gene phosphatase and tensin homolog (PTEN) and REST. Our study reveals an epigenetic mechanism that silences tumor suppressor genes and restricts REST expression in time after injury to promote axon regeneration.

scholarly journals Influence of Benzo(a)pyrene on Different Epigenetic Processes

2021 ◽  
Vol 22 (24) ◽  
pp. 13453
Author(s):  
Bożena Bukowska ◽  
Paulina Sicińska
Keyword(s):  
Lung Cancer ◽  
Dna Methylation ◽  
Histone Deacetylases ◽  
Polyaromatic Hydrocarbons ◽  
Methylation Status ◽  
Underlying Mechanism ◽  
Epidemiological Studies ◽  
Dna Methyltransferases ◽  
Epigenetic Changes ◽  
Marine Medaka

Epigenetic changes constitute one of the processes that is involved in the mechanisms of carcinogenicity. They include dysregulation of DNA methylation processes, disruption of post-translational patterns of histone modifications, and changes in the composition and/or organization of chromatin. Benzo(a)pyrene (BaP) influences DNA methylation and, depending on its concentrations, as well as the type of cell, tissue and organism it causes hypomethylation or hypermethylation. Moreover, the exposure to polyaromatic hydrocarbons (PAHs), including BaP in tobacco smoke results in an altered methylation status of the offsprings. Researches have indicated a potential relationship between toxicity of BaP and deregulation of the biotin homeostasis pathway that plays an important role in the process of carcinogenesis. Animal studies have shown that parental-induced BaP toxicity can be passed on to the F1 generation as studied on marine medaka (Oryzias melastigma), and the underlying mechanism is likely related to a disturbance in the circadian rhythm. In addition, ancestral exposure of fish to BaP may cause intergenerational osteotoxicity in non-exposed F3 offsprings. Epidemiological studies of lung cancer have indicated that exposure to BaP is associated with changes in methylation levels at 15 CpG; therefore, changes in DNA methylation may be considered as potential mediators of BaP-induced lung cancer. The mechanism of epigenetic changes induced by BaP are mainly due to the formation of CpG-BPDE adducts, between metabolite of BaP—BPDE and CpG, which leads to changes in the level of 5-methylcytosine. BaP also acts through inhibition of DNA methyltransferases activity, as well as by increasing histone deacetylases HDACs, i.e., HDAC2 and HDAC3 activity. The aim of this review is to discuss the mechanism of the epigenetic action of BaP on the basis of the latest publications.

scholarly journals The DNA methyltransferase 1 (DNMT1) acts on neurodegeneration by modulating proteostasis-relevant intracellular processes

2020 ◽  
Author(s):  
Cathrin Bayer ◽  
Georg Pitschelatow ◽  
Nina Hannemann ◽  
Jenice Linde ◽  
Julia Reichard ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Neurodegenerative Diseases ◽  
Dna Methyltransferase ◽  
Underlying Mechanism ◽  
Dna Methyltransferases ◽  
Term Survival ◽  
Expression Studies ◽  
Autophagy Pathway ◽  
Biochemical Analyses

AbstractThe limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, as well as age-associated and neurodegenerative diseases. Subordinate to genetic networks, epigenetic mechanisms, like DNA methylation and histone modifications, are involved in the regulation of neuronal functionality, and emerge as key contributors to the pathophysiology of neurodegenerative diseases. DNA methylation, a dynamic and reversible process, is executed by DNA methyltransferases (DNMTs). DNMT1 was previously shown to regulate neuronal survival in the aged brain, whereby a DNMT1-dependent modulation of processes relevant for protein degradation was proposed as underlying mechanism. Functional proteostasis networks are a mandatory prerequisite for the functionality and long-term survival of neurons. Malfunctioning proteostasis is found, inter alia, in neurodegenerative contexts. Here, we investigated whether DNMT1 affects critical aspects of the proteostasis network by a combination of expression studies, life cell imaging and biochemical analyses. We found that DNMT1 negatively impacts retrograde trafficking and autophagy, both being involved in the clearance of aggregation-prone proteins by the aggresome-autophagy pathway. In line with this, we found that the transport of GFP-labeled mutant HTT to perinuclear regions, proposed to by cytoprotective, also depends on DNMT1. Depletion of Dnmt1 accelerated HTT perinuclear HTT aggregation and improved the survival of cells transfected with mutant HTT. This suggests that mutant HTT-induced cytotoxicity is at least in part mediated by DNMT1-dependent modulation of degradative pathways.

scholarly journals DNA Methylation Status in Cancer Disease: Modulations by Plant-Derived Natural Compounds and Dietary Interventions

Biomolecules ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 289 ◽  
Author(s):  
Karin Jasek ◽  
Peter Kubatka ◽  
Marek Samec ◽  
Alena Liskova ◽  
Karel Smejkal ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Rapid Development ◽  
Methylation Status ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanism ◽  
Preclinical Research ◽  
Gene Expressions ◽  
Wide Range

The modulation of the activity of DNA methyltransferases (DNMTs) represents a crucial epigenetic mechanism affecting gene expressions or DNA repair mechanisms in the cells. Aberrant modifications in the function of DNMTs are a fundamental event and part of the pathogenesis of human cancer. Phytochemicals, which are biosynthesized in plants in the form of secondary metabolites, represent an important source of biomolecules with pleiotropic effects and thus provide a wide range of possible clinical applications. It is well documented that phytochemicals demonstrate significant anticancer properties, and in this regard, rapid development within preclinical research is encouraging. Phytochemicals affect several epigenetic molecular mechanisms, including DNA methylation patterns such as the hypermethylation of tumor-suppressor genes and the global hypomethylation of oncogenes, that are specific cellular signs of cancer development and progression. This review will focus on the latest achievements in using plant-derived compounds and plant-based diets targeting epigenetic regulators and modulators of gene transcription in preclinical and clinical research in order to generate novel anticancer drugs as sensitizers for conventional therapy or compounds suitable for the chemoprevention clinical setting in at-risk individuals. In conclusion, indisputable anticancer activities of dietary phytochemicals linked with proper regulation of DNA methylation status have been described. However, precisely designed and well-controlled clinical studies are needed to confirm their beneficial epigenetic effects after long-term consumption in humans.

Epigenetic modifications in acute lymphoblastic leukemia: From cellular mechanisms to therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Ezzatollah Fathi ◽  
Raheleh Farahzadi ◽  
Soheila Montazersaheb ◽  
Yasin Bagheri
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
Histone Modification ◽  
Epigenetic Modification ◽  
Lymphoblastic Leukemia ◽  
Underlying Mechanism ◽  
Methylation Pattern ◽  
Epigenetic Alterations ◽  
Cellular Mechanisms ◽  
Novel Treatments

Background:: Epigenetic modification pattern is considered as a characteristic feature in blood malignancies. Modifications in the DNA methylation modulators are recurrent in lymphoma and leukemia, so that, the distinct methylation pattern defines different types of leukemia. Generally, the role of epigenetics is less understood and most investigations are focused on genetic abnormalities and cytogenic studies to develop novel treatments for patients with hematologic disorders. Recently, understanding the underlying mechanism of acute lymphoblastic leukemia (ALL), especially epigenetic altera-tions as a driving force in the development of ALL opens a new era of investigation for developing promising strategy, be-yond available conventional therapy. Objective:: This review will focus on a better understanding of the epigenetic mechanisms in cancer development and pro-gression, with an emphasis on epigenetic alterations in ALL including, DNA methylation, histone modification, and mi-croRNA alterations. Other topics that will be discussed include the use of epigenetic alterations as a promising therapeutic target in order to develop novel well-suited approaches against ALL. Conclusion:: According to the literature review, leukemogenesis of ALL is extensively influenced by epigenetic modifica-tions, particularly DNA hyper-methylation, histone modification, and miRNA alteration.

Sign in / Sign up

Export Citation Format

Share Document