scholarly journals Genome-Wide Expression of MicroRNAs Is Regulated by DNA Methylation in Hepatocarcinogenesis

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jing Shen ◽  
Shuang Wang ◽  
Abby B. Siegel ◽  
Helen Remotti ◽  
Qiao Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Potential Role ◽  
Dna Hypermethylation ◽  
Two Phase ◽  
Genome Wide ◽  
Phase Study ◽  
A Genome ◽  
Genome Wide Expression ◽  
Inactive Chromatin

Background.Previous studies, including ours, have examined the regulation of microRNAs (miRNAs) by DNA methylation, but whether this regulation occurs at a genome-wide level in hepatocellular carcinoma (HCC) is unclear.Subjects/Methods.Using a two-phase study design, we conducted genome-wide screening for DNA methylation and miRNA expression to explore the potential role of methylation alterations in miRNAs regulation.Results.We found that expressions of 25 miRNAs were statistically significantly different between tumor and nontumor tissues and perfectly differentiated HCC tumor from nontumor. Six miRNAs were overexpressed, and 19 were repressed in tumors. Among 133 miRNAs with inverse correlations between methylation and expression, 8 miRNAs (6%) showed statistically significant differences in expression between tumor and nontumor tissues. Six miRNAs were validated in 56 additional paired HCC tissues, and significant inverse correlations were observed for miR-125b and miR-199a, which is consistent with the inactive chromatin pattern found in HepG2 cells.Conclusion.These data suggest that the expressions of miR-125b and miR-199a are dramatically regulated by DNA hypermethylation that plays a key role in hepatocarcinogenesis.

scholarly journals DNA hypermethylation associated with upregulated gene expression in prostate cancer demonstrates the diversity of epigenetic regulation

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Ieva Rauluseviciute ◽  
Finn Drabløs ◽  
Morten Beck Rye
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Dna Methylation ◽  
Epigenetic Regulation ◽  
Normal Tissue ◽  
Expression Profiles ◽  
Expression Data ◽  
Dna Hypermethylation ◽  
Genome Wide ◽  
A Genome

Abstract Background Prostate cancer (PCa) has the highest incidence rates of cancers in men in western countries. Unlike several other types of cancer, PCa has few genetic drivers, which has led researchers to look for additional epigenetic and transcriptomic contributors to PCa development and progression. Especially datasets on DNA methylation, the most commonly studied epigenetic marker, have recently been measured and analysed in several PCa patient cohorts. DNA methylation is most commonly associated with downregulation of gene expression. However, positive associations of DNA methylation to gene expression have also been reported, suggesting a more diverse mechanism of epigenetic regulation. Such additional complexity could have important implications for understanding prostate cancer development but has not been studied at a genome-wide scale. Results In this study, we have compared three sets of genome-wide single-site DNA methylation data from 870 PCa and normal tissue samples with multi-cohort gene expression data from 1117 samples, including 532 samples where DNA methylation and gene expression have been measured on the exact same samples. Genes were classified according to their corresponding methylation and expression profiles. A large group of hypermethylated genes was robustly associated with increased gene expression (UPUP group) in all three methylation datasets. These genes demonstrated distinct patterns of correlation between DNA methylation and gene expression compared to the genes showing the canonical negative association between methylation and expression (UPDOWN group). This indicates a more diversified role of DNA methylation in regulating gene expression than previously appreciated. Moreover, UPUP and UPDOWN genes were associated with different compartments — UPUP genes were related to the structures in nucleus, while UPDOWN genes were linked to extracellular features. Conclusion We identified a robust association between hypermethylation and upregulation of gene expression when comparing samples from prostate cancer and normal tissue. These results challenge the classical view where DNA methylation is always associated with suppression of gene expression, which underlines the importance of considering corresponding expression data when assessing the downstream regulatory effect of DNA methylation.

scholarly journals The Potential Role of Genetic Assimilation during Maize Domestication

2017 ◽  
Author(s):  
Anne Lorant ◽  
Sarah Pedersen ◽  
Irene Holst ◽  
Matthew B. Hufford ◽  
Klaus Winter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zea Mays ◽  
Potential Role ◽  
Expression Patterns ◽  
Genetic Assimilation ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Mechanisms ◽  
Maize Domestication

ABSTRACTDomestication research has largely focused on identification of morphological and genetic differences between extant populations of crops and their wild relatives. Little attention has been paid to the potential effects of environment despite substantial known changes in climate from the time of domestication to modern day. Recent research, in which maize and teosinte (i.e., wild maize) were exposed to environments similar to the time of domestication, resulted in a plastic induction of domesticated phenotypes in teosinte and little response to environment in maize. These results suggest that early agriculturalists may have selected for genetic mechanisms that cemented domestication phenotypes initially induced by a plastic response of teosinte to environment, a process known as genetic assimilation. To better understand this phenomenon and the potential role of environment in maize domestication, we examined differential gene expression in maize (Zea mays ssp. mays) and teosinte (Zea mays ssp. parviglumis) between past and present conditions. We identified a gene set of over 2000 loci showing a change in expression across environmental conditions in teosinte and invariance in maize. In fact, overall we observed both greater plasticity in gene expression and more substantial re-wiring of expression networks in teosinte across environments when compared to maize. While these results suggest genetic assimilation played at least some role in domestication, genes showing expression patterns consistent with assimilation are not significantly enriched for previously identified domestication candidates, indicating assimilation did not have a genome-wide effect.

scholarly journals Genome-wide disruption of DNA methylation by 5-aza-2’-deoxycytidine in the parasitoid wasp Nasonia vitripennis

2018 ◽  
Author(s):  
Nicola Cook ◽  
Darren J Parker ◽  
Frances Turner ◽  
Eran Tauber ◽  
Bart A Pannebakker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Evolutionary Biology ◽  
Sex Allocation ◽  
Phenotypic Expression ◽  
Parasitoid Wasp ◽  
Nasonia Vitripennis ◽  
Genomic Conflict ◽  
Genome Wide ◽  
A Genome

AbstractDNA methylation of cytosine residues across the genome influences how genes and phenotypes are regulated in a wide range of organisms. As such, understanding the role of DNA methylation and other epigenetic mechanisms has become very much a part of mapping genotype to phenotype, a major question in evolutionary biology. Ideally, we would like to manipulate DNA methylation patterns on a genome-wide scale, to help us to elucidate the role that epigenetic modifications play in phenotypic expression. Recently, the demethylating agent 5-aza-2’-deoxycytidine (5-aza-dC; commonly used in the epigenetic treatment of certain cancers), has been deployed to explore the epigenetic regulation of a number of traits of interest to evolutionary ecologists, including facultative sex allocation in the parasitoid wasp Nasonia vitripennis. In a recent study, we showed that treatment with 5-aza-dC did not ablate the facultative sex allocation response in Nasonia, but shifted the patterns of sex allocation in a way predicted by genomic conflict theory. This was the first (albeit indirect) experimental evidence for genomic conflict over sex allocation facilitated by DNA methylation. However, that work lacked direct evidence of the effects of 5-aza-dC on DNA methylation, and indeed the effect of the chemical has since been questioned in Nasonia. Here, using whole-genome bisulphite sequencing of more than 4 million CpGs, across more than 11,000 genes, we demonstrate unequivocally that 5-aza-dC disrupts methylation on a large scale across the Nasonia vitripennis genome. We show that the disruption can lead to both hypo- and hyper-methylation, may vary across tissues and time of sampling, and that the effects of 5-aza-dC are context- and sequence specific. We conclude that 5-aza-dC does indeed have the potential to be repurposed as a tool for studying the role of DNA methylation in evolutionary ecology, whilst many details of its action remain to be discovered.Author SummaryShedding light on the mechanistic basis of phenotypes is a major aim in the field of evolutionary biology. If we understand how phenotypes are controlled at the molecular level, we can begin to understand how evolution has shaped that phenotype and conversely, how genetic architecture may constrain trait evolution. Epigenetic markers (such as DNA methylation) also influence phenotypic expression by regulating how and when genes are expressed. Recently, 5-aza-2’-deoxycytidine (5-aza-dC), a hypomethylating agent used in the treatment of certain cancers, has been used to explore the epigenetic regulation of traits of interest to evolutionary ecologists. Previously, we used 5-aza-dC to validate a role for DNA methylation in facultative sex allocation behaviour in the parasitoid wasp Nasonia vitripennis. However, the direct effects of the chemical were not examined at that point and its efficacy in insects was questioned. Here, we demonstrate that 5-aza-dC disrupts DNA methylation on a genome-wide scale in a context- and sequence-specific manner and results in both hypo- and hyper-methylation. Our work demonstrates that 5-aza-dC has the potential to be repurposed as a tool for studying the role of DNA methylation in phenotypic expression.

scholarly journals Epigenetics biomarkers of delirium: immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients

2019 ◽  
Author(s):  
Taku Saito ◽  
Hiroyuki Toda ◽  
Gabrielle N. Duncan ◽  
Sydney S. Jellison ◽  
Tong Yu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Network Analysis ◽  
Tnf Alpha ◽  
Epigenetic Biomarkers ◽  
Genome Wide ◽  
A Genome ◽  
Significant Difference ◽  
Dnam Level

ABSTRACTBackgroundThe authors previously hypothesized the role of epigenetics in pathophysiology of delirium, and tested DNA methylation (DNAm) change among pro-inflammatory cytokines along with aging in blood, glia and neuron. The authors reported that DNAm level of the TNF-alpha decreases along with aging in blood and glia, but not in neuron; however, DNAm differences between delirium cases and non-delirium controls have not been investigated directly. Therefore, in the present study, DNAm differences in blood between delirium patients and controls without delirium were examined.MethodsA case-control study with 92 subjects was conducted. Whole blood samples were collected and genome-wide DNAm was measured by the Infinium HumanMethylationEPIC BeadChip arrays. The correlation between DNAm levels in the TNF-alpha and age, network analysis, and the correlation between age and DNAm age were tested.ResultsOnly delirium cases showed 3 CpGs sites in the TNF-alpha significantly correlated to age after multiple corrections. A genome-wide significant CpG site near the gene of LDLRAD4 was identified. In addition, network analysis showed several significant pathways with false discovery rate adjusted p-value < 0.05. The top pathway with GO was immune response, and the second top pathway with KEGG was cholinergic synapse. Although there was no statistically significant difference, DNAm age among non-delirium controls showed “slower aging” compared to delirium cases.ConclusionsDNAm differences were shown both at gene and network levels between delirium cases and non-delirium controls. This finding indicates that DNAm status in blood has a potential to be used as epigenetic biomarkers for delirium.

P002 Specific genome editing to model hypermethylation of the SP140 gene that associates to Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S129-S130
Author(s):  
I Hageman ◽  
A Li Yim ◽  
V Joustra ◽  
M Ghiboub ◽  
K Gecse ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Protein Function ◽  
Regulatory Region ◽  
Methyl Groups ◽  
Nucleotide Polymorphisms ◽  
Dna Hypermethylation ◽  
A Genome

Abstract Background SP140 (Speckled 140 KDa) encodes an epigenetic reader protein with an immune restricted expression, that binds to epigenetically modified (acetylated and methylated) histones and thereby regulates expression of large gene sets, including pro-inflammatory cytokines, in innate immune cells. SP140 is implicated in CD because single nucleotide polymorphisms, as well as defective protein function are associated with CD and marks anti-TNF response. Through a genome-wide methylation screen of Crohn’s disease (CD) patients peripheral blood, we identified two hypermethylated positions in SP140 locus associated with CD patients. We hypothesise that this DNA hypermethylation at the SP140 locus controls SP140 expression in CD patients contributing to their colitis development. Methods To address the role of SP140 DNA methylation, we used CRISPR ‘dead’ Cas9 (dCas9) epigenome-editing for specifically adding methyl groups (dCas9-DNMT) or removing methyl groups (dCas9-TET) in monocyte cell line THP1. We developed guide RNAs complementary to the gene expression regulatory region of the SP140 gene. With lentiviral delivery, we transduced THP-1 cells with guide RNA-lentiviruses, and with dCas9-DNMT or dCas9-TET lentiviruses. We assessed the level of SP140 methylation using bisulphite Sanger sequencing and the effect of methylation intervention of SP140 using qPCR and ELISA for SP140, IL-6, TNFα, IL-1β. Results We observed that SP140 gene in THP-1 cells under control conditions contained little methylated CpG sites. We induced sp140 hypermethylation through transduction of dCas9-DNMT. We validated hypermethylation of the two SP140 CpGs in transduced THP1 cells, thus mimicking the observed hypermethylation in CD patients cells. SP140 hypermethylation in THP1 cells polarised into M1 macrophages and stimulated with lipoteichoic acid (TLR-2 ligand), displayed a decrease of TNFα and (p = 0.042) protein levels. Similarly, we showed a decrease of TNFα (p = 0.02) and IL-6 (p = 0.03) protein release after transduction dCas9-DNMT and stimulation with LPS or Zymosan (TLR-2/4 ligand). Conclusion In this study, we demonstrated that editing SP140 gene methylation through CRISPR-dCAS9 technology allows modelling of the relevance of epigenetic marks for CD aetiology. Through methylome editing, we could affect the expression of CD-associated pro-inflammatory genes. Our dCas9 technique will allow us to investigate the role of DNA-methylation in the aetiology of CD.

scholarly journals Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Michael A. Levy ◽  
David B. Beck ◽  
Kay Metcalfe ◽  
Sofia Douzgou ◽  
Sivagamy Sithambaram ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Neurodevelopmental Disorder ◽  
Dna Demethylation ◽  
Dna Hypermethylation ◽  
Direct Role ◽  
Biologically Relevant ◽  
Pathogenic Variants ◽  
Genome Wide ◽  
A Genome

AbstractTET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease

2018 ◽  
Vol 32 (10) ◽  
pp. 5215-5226 ◽  
Author(s):  
Benjamin P. Larkin ◽  
Sarah J. Glastras ◽  
Hui Chen ◽  
Carol A. Pollock ◽  
Sonia Saad
Keyword(s):  
Chronic Kidney Disease ◽  
Dna Methylation ◽  
Kidney Disease ◽  
Potential Role ◽  
Demethylating Agents

scholarly journals A Genome-Wide Analysis of Pathogenesis-Related Protein-1 (PR-1) Genes from Piper nigrum Reveals Its Critical Role during Phytophthora capsici Infection

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1007
Author(s):  
Divya Kattupalli ◽  
Asha Sreenivasan ◽  
Eppurathu Vasudevan Soniya
Keyword(s):  
Phytophthora Capsici ◽  
Regulatory Elements ◽  
Piper Nigrum ◽  
Binding Motif ◽  
Altered Expression ◽  
Genome Wide ◽  
A Genome ◽  
Pathogenesis Related Protein ◽  
Pathogenesis Related

Black pepper (Piper nigrum L.) is a prominent spice that is an indispensable ingredient in cuisine and traditional medicine. Phytophthora capsici, the causative agent of footrot disease, causes a drastic constraint in P. nigrum cultivation and productivity. To counterattack various biotic and abiotic stresses, plants employ a broad array of mechanisms that includes the accumulation of pathogenesis-related (PR) proteins. Through a genome-wide survey, eleven PR-1 genes that belong to a CAP superfamily protein with a caveolin-binding motif (CBM) and a CAP-derived peptide (CAPE) were identified from P. nigrum. Despite the critical functional domains, PnPR-1 homologs differ in their signal peptide motifs and core amino acid composition in the functional protein domains. The conserved motifs of PnPR-1 proteins were identified using MEME. Most of the PnPR-1 proteins were basic in nature. Secondary and 3D structure analyses of the PnPR-1 proteins were also predicted, which may be linked to a functional role in P. nigrum. The GO and KEGG functional annotations predicted their function in the defense responses of plant-pathogen interactions. Furthermore, a transcriptome-assisted FPKM analysis revealed PnPR-1 genes mapped to the P. nigrum-P. capsici interaction pathway. An altered expression pattern was detected for PnPR-1 transcripts among which a significant upregulation was noted for basic PnPR-1 genes such as CL10113.C1 and Unigene17664. The drastic variation in the transcript levels of CL10113.C1 was further validated through qRT-PCR and it showed a significant upregulation in infected leaf samples compared with the control. A subsequent analysis revealed the structural details, phylogenetic relationships, conserved sequence motifs and critical cis-regulatory elements of PnPR-1 genes. This is the first genome-wide study that identified the role of PR-1 genes during P. nigrum-P. capsici interactions. The detailed in silico experimental analysis revealed the vital role of PnPR-1 genes in regulating the first layer of defense towards a P. capsici infection in Panniyur-1 plants.

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