scholarly journals METHYLOME DYNAMICS UPON PROTEASOME INHIBITION BY THE PSEUDOMONAS VIRULENCE FACTOR SYRINGOLIN A

2021 ◽  
Author(s):  
S Grob ◽  
DMV Bonnet ◽  
L Tirot ◽  
PE Jullien
Keyword(s):  
Dna Methylation ◽  
Virulence Factor ◽  
De Novo ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Epigenetic Mark ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Bacterial Effectors ◽  
Transcriptional Start Sites

AbstractDNA methylation is an important epigenetic mark required for proper gene expression and silencing of transposable elements. DNA methylation patterns can be modified by environmental factors such as pathogen infection, where modification of DNA methylation can be associated with plant resistance. To counter the plant defense pathways, pathogens produce effectors molecule, several of which act as proteasome inhibitors. Here we investigated the effect of proteasome inhibition by the bacterial virulence factor Syringolin A on genome-wide DNA methylation. We show that Syringolin A treatment results in an increase of DNA methylation at centromeric and pericentromeric regions of Arabidopsis chromosomes. We identify several CHH DMRs that are enriched in the proximity of transcriptional start sites. Syringolin A treatment does not result in significant changes in small RNA composition. However, significant changes in genome transcriptional activity can be observed, including a strong upregulation of resistance genes that are located on chromosomal arms. We hypothesize that DNA methylation changes could be linked to the upregulation of some atypical members of the de novo DNA methylation pathway: AGO3, AGO9 and DRM1. Our data suggests that modification of genome-wide DNA methylation resulting from an inhibition of the proteasome by bacterial effectors could be part of a epi-genomic arms race against pathogens.

scholarly journals Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Shir Toubiana ◽  
Miriam Gagliardi ◽  
Mariarosaria Papa ◽  
Roberta Manco ◽  
Maty Tzukerman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Pharmacological Intervention ◽  
Icf Syndrome ◽  
Genome Wide ◽  
Mammalian Genomes ◽  
Induced Pluripotent ◽  
Methylation Patterns

DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human DNMT3B disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected DNMT3B mutations in induced pluripotent stem cells from ICF1 patients. Focusing on repetitive regions, we show that in contrast to pericentromeric repeats, which reacquire normal methylation, the majority of subtelomeres acquire only partial DNA methylation and, accordingly, the ICF1 telomeric phenotype persists. Subtelomeres resistant to de novo methylation were characterized by abnormally high H3K4 trimethylation (H3K4me3), and short-term reduction of H3K4me3 by pharmacological intervention partially restored subtelomeric DNA methylation. These findings demonstrate that the abnormal epigenetic landscape established in ICF1 cells restricts the recruitment of DNMT3B, and suggest that rescue of epigenetic diseases with genome-wide disruptions will demand further manipulation beyond mutation correction.

scholarly journals Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

2021 ◽  
Author(s):  
Jean S Fain ◽  
Axelle Loriot ◽  
Anna Diacofotaki ◽  
Aurelie Van Tongelen ◽  
Charles De Smet
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Tumor Development ◽  
Epigenetic Mark ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Bioinformatics Analyses ◽  
Genomic Regions ◽  
Methylation Patterns

DNA methylation is an epigenetic mark associated with gene repression. It is now well established that tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) of methylation marks in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark known to be deposited during progression of the transcription machinery and to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of increased DNA methylation in the MAGEA6/GABRA3 locus. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo- and hypermethylation. In several of these loci, DNA hypermethylation affected tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

scholarly journals Developmental Genome-Wide DNA Methylation Asymmetry Between Mouse Placenta and Embryo

2019 ◽  
Author(s):  
LM Legault ◽  
K Doiron ◽  
A Lemieux ◽  
M Caron ◽  
D Chan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Prenatal Development ◽  
Methyltransferase Activity ◽  
Developmental Program ◽  
Genome Wide ◽  
Early Embryos ◽  
Somatic Tissues ◽  
Main Driver ◽  
Methylation Patterns

ABSTRACTIn early embryos, DNA methylation is remodelled to initiate the developmental program but for mostly unknown reasons, methylation marks are acquired unequally between embryonic and placental cells. To better understand this, we generated high-resolution DNA methylation maps of mouse mid-gestation (E10.5) embryo and placenta. We uncovered specific subtypes of differentially methylated regions (DMRs) that contribute directly to the developmental asymmetry existing between mid-gestation embryonic and placental DNA methylation patterns. We show that the asymmetry occurs rapidly during the acquisition of marks in the post-implanted conceptus (E3.5-E6.5), and that these patterns are long-lasting across subtypes of DMRs throughout prenatal development and in somatic tissues. We reveal that at the peri-implantation stages, the de novo methyltransferase activity of DNMT3B is the main driver of methylation marks on asymmetric DMRs, and that DNMT3B can largely compensate for lack of DNMT3A in the epiblast and extraembryonic ectoderm, whereas DNMT3A can only partially compensate in the absence of DNMT3B. However, as development progresses and as DNMT3A becomes the principal de novo methyltransferase, the compensatory DNA methylation mechanism of DNMT3B on DMRs becomes less effective.

scholarly journals Global reinforcement of DNA methylation through enhancement of RNA-directed DNA methylation ensures sexual reproduction in rice

2020 ◽  
Author(s):  
Lili Wang ◽  
Longjun Zeng ◽  
Kezhi Zheng ◽  
Tianxin Zhu ◽  
Yumeng Yin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sexual Reproduction ◽  
De Novo ◽  
Rice Genome ◽  
Biological Significance ◽  
Reproductive Organs ◽  
Epigenetic Mark ◽  
Small Interfering Rnas ◽  
Genome Wide ◽  
Global Increase

AbstractDNA methylation is an important epigenetic mark that regulates the expression of genes and transposons. RNA-directed DNA methylation (RdDM) is the main molecular pathway responsible for de novo DNA methylation in plants. In Arabidopsis, however, mutations in RdDM genes cause no visible developmental defects, which raising the question of the biological significance of RdDM in plant development. Here, we isolated and cloned Five Elements Mountain 1 (FEM1), which encodes an RNA-dependent RNA polymerase. Mutation in FEM1 substantially decreased genome-wide CHH methylation levels and abolished the accumulation of 24-nt small interfering RNAs. Moreover, male and female reproductive development was disturbed, which led to the sterility of fem1 mutants. In wild-type (WT) plants but not in fem1 mutants, genome-wide CHH DNA methylation levels were greater in panicles, stamens, and pistils than in seedlings. The global increase of methylation in reproductive organs of the WT was attributed to enhancement of RdDM activity including FEM1 activity. More than half of all encoding genes in the rice genome overlapped with hypermethylated regions in the sexual organs of the WT, and many of them appear to be directly regulated by an increase in DNA methylation.Our results demonstrate that a global increase of DNA methylation through enhancement of RdDM activity in reproductive organs ensures sexual reproduction of rice.

scholarly journals Common alleles of CMT2 and NRPE1 are major determinants of de novo DNA methylation variation in Arabidopsis thaliana

2019 ◽  
Author(s):  
Eriko Sasaki ◽  
Taiji Kawakatsu ◽  
Joseph Ecker ◽  
Magnus Nordborg
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Cytosine Methylation ◽  
De Novo ◽  
Association Studies ◽  
Published Data ◽  
Epigenetic Mark ◽  
Stabilizing Selection ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractDNA cytosine methylation is an epigenetic mark associated with silencing of transposable elements (TEs) and heterochromatin formation. In plants, it occurs in three sequence contexts: CG, CHG, and CHH (where H is A, T, or C). The latter does not allow direct inheritance of methylation during DNA replication due to lack of symmetry, and methylation must therefore be re-established every cell generation. Genome-wide association studies (GWAS) have previously shown that CMT2 and NRPE1 are major determinants of genome-wide patterns of TE CHH-methylation. Here we instead focus on CHH-methylation of individual TEs and TE-families, allowing us to identify the pathways involved in CHH-methylation simply from natural variation and confirm the associations by comparing them with mutant phenotypes. Methylation at TEs targeted by the RNA-directed DNA methylation (RdDM) pathway is unaffected by CMT2 variation, but is strongly affected by variation at NRPE1, which is largely responsible for the longitudinal cline in this phenotype. In contrast, CMT2-targeted TEs are affected by both loci, which jointly explain 7.3% of the phenotypic variation (13.2% of total genetic effects). There is no longitudinal pattern for this phenotype, however, because the geographic patterns appear to compensate for each other in a pattern suggestive of stabilizing selection.Author SummaryDNA methylation is a major component of transposon silencing, and essential for genomic integrity. Recent studies revealed large-scale geographic variation as well as the existence of major trans-acting polymorphisms that partly explained this variation. In this study, we re-analyze previously published data (The 1001 Epigenomes), focusing on de novo DNA methylation patterns of individual TEs and TE families rather than on genome-wide averages (as was done in previous studies). GWAS of the patterns reveals the underlying regulatory networks, and allowed us to comprehensively characterize trans-regulation of de novo DNA methylation and its role in the striking geographic pattern for this phenotype.

scholarly journals A model for the aberrant DNA methylomes in aging cells and cancer cells

2019 ◽  
Vol 47 (4) ◽  
pp. 997-1003 ◽  
Author(s):  
Huiming Zhang ◽  
Kang Zhang ◽  
Jian-Kang Zhu
Keyword(s):  
Dna Methylation ◽  
Cancer Cells ◽  
Developmental Stages ◽  
Methylation Pattern ◽  
Epigenetic Mark ◽  
Dna Hypomethylation ◽  
Genome Wide ◽  
Abnormal Cells ◽  
Genomic Regions ◽  
Methylation Patterns

Abstract DNA methylation at the fifth position of cytosine is a major epigenetic mark conserved in plants and mammals. Genome-wide DNA methylation patterns are dynamically controlled by integrated activities of establishment, maintenance, and removal. In both plants and mammals, a pattern of global DNA hypomethylation coupled with increased methylation levels at some specific genomic regions arises at specific developmental stages and in certain abnormal cells, such as mammalian aging cells and cancer cells as well as some plant epigenetic mutants. Here we provide an overview of this distinct DNA methylation pattern in mammals and plants, and propose that a methylstat, which is a cis-element responsive to both DNA methylation and active demethylation activities and controlling the transcriptional activity of a key DNA methylation regulator, can help to explain the enigmatic DNA methylation patterns in aging cells and cancer cells.

scholarly journals The Identification of a Novel Fucosidosis-Associated FUCA1 Mutation: A Case of a 5-Year-Old Polish Girl with Two Additional Rare Chromosomal Aberrations and Affected DNA Methylation Patterns

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 74
Author(s):  
Agnieszka Domin ◽  
Tomasz Zabek ◽  
Aleksandra Kwiatkowska ◽  
Tomasz Szmatola ◽  
Anna Deregowska ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chromosomal Aberrations ◽  
De Novo ◽  
Methylation Status ◽  
Autosomal Recessive Disorder ◽  
Pathogenic Variants ◽  
Genome Wide ◽  
Base Pair Deletion ◽  
Biallelic Mutations ◽  
Methylation Patterns

Fucosidosis is a rare neurodegenerative autosomal recessive disorder, which manifests as progressive neurological and psychomotor deterioration, growth retardation, skin and skeletal abnormalities, intellectual disability and coarsening of facial features. It is caused by biallelic mutations in FUCA1 encoding the α-L-fucosidase enzyme, which in turn is responsible for degradation of fucose-containing glycoproteins and glycolipids. FUCA1 mutations lead to severe reduction or even loss of α-L-fucosidase enzyme activity. This results in incomplete breakdown of fucose-containing compounds leading to their deposition in different tissues and, consequently, disease progression. To date, 36 pathogenic variants in FUCA1 associated with fucosidosis have been documented. Among these are three splice site variants. Here, we report a novel fucosidosis-related 9-base-pair deletion (NG_013346.1:g.10233_10241delACAGGTAAG) affecting the exon 3/intron 3 junction within a FUCA1 sequence. This novel pathogenic variant was identified in a five-year-old Polish girl with a well-defined pattern of fucosidosis symptoms. Since it is postulated that other genetic, nongenetic or environmental factors can also contribute to fucosidosis pathogenesis, we performed further analysis and found two rare de novo chromosomal aberrations in the girl’s genome involving a 15q11.1-11.2 microdeletion and an Xq22.2 gain. These abnormalities were associated with genome-wide changes in DNA methylation status in the epigenome of blood cells.

scholarly journals Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

2018 ◽  
Author(s):  
Aaron R Jeffries ◽  
Reza Maroofian ◽  
Claire G. Salter ◽  
Barry A. Chioza ◽  
Harold E. Cross ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Biological Aging ◽  
Growth Disorders ◽  
Sotos Syndrome ◽  
Dna Hypomethylation ◽  
Genome Wide ◽  
Epigenetic Aging ◽  
Methylation Patterns

AbstractGermline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. Notably, these findings were most striking in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.

scholarly journals Flanking sequence preference modulates de novo DNA methylation in the mouse genome

2020 ◽  
Author(s):  
Izaskun Mallona ◽  
Ioana Mariuca Ilie ◽  
Massimiliano Manzo ◽  
Amedeo Caflisch ◽  
Tuncay Baubec
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Cell Types ◽  
Dna Methyltransferases ◽  
Flanking Sequence ◽  
Base Pairs ◽  
Genome Wide ◽  
Dynamics Simulations ◽  
Methylation Patterns ◽  
Different Cell Types

AbstractMammalian de novo DNA methyltransferases (DNMT) are responsible for the establishment of cell-type-specific DNA methylation in healthy and diseased tissues. Through genome-wide analysis of de novo methylation activity in murine stem cells we uncover that DNMT3A prefers to methylate CpGs followed by cytosines or thymines, while DNMT3B predominantly methylates CpGs followed by guanines or adenines. These signatures are further observed at non-CpG sites, resembling methylation context observed in specialised cell types, including neurons and oocytes. We further show that these preferences are not mediated by the differential recruitment of the two de novo DNMTs to the genome but are resulting from structural differences in their catalytic domains. Molecular dynamics simulations suggest that, in case of DNMT3A, the preference is due to favourable polar interactions between the flexible Arg836 side chain and the guanine that base-pairs with the cytosine following the CpG. This context-dependent de novo DNA methylation provides additional insights into the complex regulation of methylation patterns in different cell types.

scholarly journals Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Todd R. Robeck ◽  
Zhe Fei ◽  
Ake T. Lu ◽  
Amin Haghani ◽  
Eve Jourdain ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Age Estimation ◽  
Species Conservation ◽  
Genome Wide ◽  
Epigenetic Aging ◽  
Highly Correlated ◽  
Methylation Patterns ◽  
Cg Dinucleotides ◽  
Free Ranging ◽  
Unique Species

AbstractThe development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

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