scholarly journals STEM-27. miR-10b-5p MODULATES 5hmC EXPRESSION AND THE STEM-LIKE PHENOTYPE IN GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii202-ii202
Author(s):  
Harmon Khela ◽  
Sweta Sudhir ◽  
Maria Lugo-Fagundo ◽  
Bachchu Lal ◽  
Hernando Lopez-Bertoni ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cell Markers ◽  
Tumor Initiation ◽  
Epigenetic Alterations ◽  
Sox2 Expression ◽  
Initiation And Propagation ◽  
Xenograft Models ◽  
Non Coding Rnas ◽  
Methylation Patterns ◽  
Sphere Formation

Abstract Epigenetic alterations such as DNA methylation and dysregulation of non-coding RNAs (e.g. miRNAs) are found in all types of cancer and are thought to play important roles in tumorigenesis. GBM is characterized by small subsets of cells, referred to as glioma stem cells (GSCs), that display stem-like properties implicated in tumor initiation, therapeutic resistance, and recurrence. DNA methylation patterns are altered in GBM and GSCs and are thought to play critical roles in tumor initiation and propagation. DNA methylation is a reversible process catalyzed, in part, by the ten-eleven translocation (TET) family of enzymes. These enzymes function as deoxygenases that catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Multiple studies found negative correlations between 5hmC levels and glioma grade and loss of 5hmC correlates with poor prognosis of GBM patients. However, the mechanisms leading to the loss of 5hmC in glioma and the role this phenomenon plays in gliomagenesis remains poorly understood. We found that Sox2 expression decreases TET2 expression and its product 5hmC in GSCs and identified miR-10b-5p as a molecular intermediary of this process. We show that miR-10b-5p expression is high in GBM compared to non-tumor in clinical specimens and high levels of this miRNA correlate with poor patient outcome. Expression of transgenic miR-10b-5p enhanced sphere formation capacity of GSCs and the expression of stem cell markers and drivers. Additionally, using a combination of molecular and biochemical endpoints, we show that miR-10b-5p modifies 5hmC levels by regulating TET2 in GSCs. Finally, we show that repression of miR-10b-5p increases 5hmC levels and inhibits tumor propagation in GBM xenograft models. Taken together, these results present a new molecular mechanism that controls 5hmC and the tumor propagating capacity of GSCs and suggests that miR-10b-5p inhibition and other strategies for enhancing TET2 function can be developed to treat GBM.

scholarly journals DNA methylation patterns of protein-coding genes and long non-coding RNAs in males with schizophrenia

2015 ◽  
Vol 12 (5) ◽  
pp. 6568-6576 ◽  
Author(s):  
QI LIAO ◽  
YUNLIANG WANG ◽  
JIA CHENG ◽  
DONGJUN DAI ◽  
XINGYU ZHOU ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Non Coding Rnas ◽  
Methylation Patterns

scholarly journals The Effects of Maternal and Postnatal Dietary Methyl Nutrients on Epigenetic Changes that Lead to Non-Communicable Diseases in Adulthood

2020 ◽  
Vol 21 (9) ◽  
pp. 3290 ◽  
Author(s):  
Raniru S. Randunu ◽  
Robert F. Bertolo
Keyword(s):  
Dna Methylation ◽  
Metabolic Pathways ◽  
Dietary Intervention ◽  
Infant Nutrition ◽  
Communicable Diseases ◽  
Epigenetic Alterations ◽  
Non Communicable Diseases ◽  
Nutrient Manipulation ◽  
Methylation Patterns ◽  
Epigenetic Patterns

The risk for non-communicable diseases in adulthood can be programmed by early nutrition. This programming is mediated by changes in expression of key genes in various metabolic pathways during development, which persist into adulthood. These developmental modifications of genes are due to epigenetic alterations in DNA methylation patterns. Recent studies have demonstrated that DNA methylation can be affected by maternal or early postnatal diets. Because methyl groups for methylation reactions come from methionine cycle nutrients (i.e., methionine, choline, betaine, folate), deficiency or supplementation of these methyl nutrients can directly change epigenetic regulation of genes permanently. Although many studies have described the early programming of adult diseases by maternal and infant nutrition, this review discusses studies that have associated early dietary methyl nutrient manipulation with direct effects on epigenetic patterns that could lead to chronic diseases in adulthood. The maternal supply of methyl nutrients during gestation and lactation can alter epigenetics, but programming effects vary depending on the timing of dietary intervention, the type of methyl nutrient manipulated, and the tissue responsible for the phenotype. Moreover, the postnatal manipulation of methyl nutrients can program epigenetics, but more research is needed on whether this approach can rescue maternally programmed offspring.

scholarly journals Analysis of DNA Methylation Patterns Associated with In Vitro Propagated Globe Artichoke Plants Using an EpiRADseq-Based Approach

Genes ◽  
2019 ◽  
Vol 10 (4) ◽  
pp. 263 ◽  
Author(s):  
Elisa Cerruti ◽  
Cinzia Comino ◽  
Alberto Acquadro ◽  
Gianpiero Marconi ◽  
Anna Maria Repetto ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Methylation Status ◽  
Transcriptional Analysis ◽  
Globe Artichoke ◽  
Epigenetic Alterations ◽  
Coding Regions ◽  
Methylation Patterns ◽  
Reproductive Processes ◽  
Photosynthesis Regulation

Globe artichoke represents one of the main horticultural species of the Mediterranean basin, and ‘Spinoso sardo’ is the most widespread and economically relevant varietal type in Sardinia, Italy. In the last decades, in vitro culture of meristematic apices has increased the frequency of aberrant plants in open-field production. These off-type phenotypes showed highly pinnate-parted leaves and late inflorescence budding, and emerged from some branches of the true-to-type ‘Spinoso sardo’ plants. This phenomenon cannot be foreseen and is reversible through generations, suggesting the occurrence of epigenetic alterations. Here, we report an exploratory study on DNA methylation patterns in off-type/true-to-type globe artichoke plants, using a modified EpiRADseq technology, which allowed the identification of 2,897 differentially methylated loci (DML): 1,998 in CG, 458 in CHH, and 441 in CHG methylation contexts of which 720, 88, and 152, respectively, were in coding regions. Most of them appeared involved in primary metabolic processes, mostly linked to photosynthesis, regulation of flower development, and regulation of reproductive processes, coherently with the observed phenotype. Differences in the methylation status of some candidate genes were integrated with transcriptional analysis to test whether these two regulation levels might interplay in the emergence and spread of the ‘Spinoso sardo’ non-conventional phenotype.

scholarly journals Non-coding RNAs and DNA methylation in plants

2014 ◽  
Vol 1 (2) ◽  
pp. 219-229 ◽  
Author(s):  
Yuanyuan Zhao ◽  
Xuemei Chen
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Genome Integrity ◽  
Non Coding Rnas ◽  
Methylation Patterns

Abstract Cytosine DNA methylation is an epigenetic modification in eukaryotes that maintains genome integrity and regulates gene expression. The DNA methylation patterns in plants are more complex than those in animals, and plants and animals have common as well as distinct pathways in regulating DNA methylation. Recent studies involving genetic, molecular, biochemical and genomic approaches have greatly expanded our knowledge of DNA methylation in plants. The roles of many proteins as well as non-coding RNAs in DNA methylation have been uncovered.

scholarly journals Residual DNA methylation at remission is prognostic in adult Philadelphia chromosome–negative acute lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 1892-1898 ◽  
Author(s):  
Hui Yang ◽  
Tapan Kadia ◽  
Lianchun Xiao ◽  
Carlos E. Bueso-Ramos ◽  
Koyu Hoshino ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Lymphocytic Leukemia ◽  
Philadelphia Chromosome ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Aberrant Methylation ◽  
Epigenetic Alterations ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns ◽  
Standard Risk

Pretreatment aberrant DNA methylation patterns are stable at time of relapse in acute lymphocytic leukemia (ALL). We hypothesized that the detection of residual methylation alterations at the time of morphologic remission may predict for worse prognosis. We developed a real-time bisulfite polymerase chain reaction assay and analyzed the methylation levels of p73, p15, and p57KIP2 at the time of initial remission in 199 patients with Philadelphia chromosome-negative and MLL− ALL. Residual p73 methylation was detected in 18 (9.5%) patients, p15 in 33 (17.4%), and p57KIP2 in 7 (3.7%); 140 (74%) patients had methylation of 0 genes and 48 (25%) of more than or equal to 1 gene. In 123 (65%) patients, matched pretreatment samples were also studied and compared with remission ones: in 82 of those with initial aberrant methylation of at least one gene, 59 (72%) had no detectable methylation at remission and 23 (28%) had detectable residual methylation. By multivariate analysis, the presence of residual p73 methylation was associated with a significant shorter duration of first complete remission (hazard ratio = 2.68, P = .003) and overall survival (hazard ratio = 2.69, P = .002). In conclusion, detection of epigenetic alterations allows the identification of patients with ALL with standard risk but with poor prognosis.

scholarly journals Clopidogrel Resistance Is Associated With DNA Methylation of Genes From Whole Blood of Humans

2021 ◽  
Vol 11 ◽  
Author(s):  
Jin Yang ◽  
Qinglin Yu ◽  
Zhifeng Xu ◽  
Nan Zheng ◽  
Jinyan Zhong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Platelet Reactivity ◽  
Future Research ◽  
Epigenetic Alterations ◽  
Biological Regulation ◽  
Clopidogrel Resistance ◽  
Methylation Patterns ◽  
And Control ◽  
The Relationship ◽  
Genomic Methylation

Antiplatelet therapy has become a cornerstone in the treatment of coronary heart disease (CHD). However, due to high-residual-platelet-reactivity, clopidogrel resistance (CR) is a common phenomenon, and it is rarely known about the relationship between CR and epigenetic changes. This study compared the whole genomic methylation patterns of blood samples from patients with CR (n = 6) and non-CR (n = 6) with the Human Methylation 850K BeadChip assay. We explored differentially methylated CpG sites, genes, and pathways using bioinformatics profiling. The CR and control groups showed significantly different DNA methylation at 7,098 sites, with 979 sites showing hypermethylation and 6,119 sites showing hypomethylation. The pyrosequencing method was used to validate four differentially methylated CpG loci (cg23371584, cg15971518, cg04481923, cg22507406), confirming that DNA methylation was associated with the risk of CR (30 CR vs. 30 non-CR). The relative mRNA expression of the four genes (BTG2, PRG2, VTRNA2-1, PER3) corresponding to the loci above was also associated with CR, suggesting that alterations in DNA methylation may affect the expression of these four genes, eventually resulting in CR. Additionally, differentially methylated sites are partially related to genes and pathways that play key roles in process of circadian entrainment, insulin secretion, and so on. Hence, the mechanism and biological regulation of CR might be reflected through these epigenetic alterations, but future research will need to address the causal relationships.

scholarly journals Epigenome Chaos: Stochastic and Deterministic DNA Methylation Events Drive Cancer Evolution

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1800
Author(s):  
Giusi Russo ◽  
Alfonso Tramontano ◽  
Ilaria Iodice ◽  
Lorenzo Chiariotti ◽  
Antonio Pezone
Keyword(s):  
Dna Methylation ◽  
Tumor Heterogeneity ◽  
Tumor Evolution ◽  
Aberrant Methylation ◽  
Epigenetic Alterations ◽  
Cancer Evolution ◽  
Cancer Types ◽  
Chromatin Proteins ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns

Cancer evolution is associated with genomic instability and epigenetic alterations, which contribute to the inter and intra tumor heterogeneity, making genetic markers not accurate to monitor tumor evolution. Epigenetic changes, aberrant DNA methylation and modifications of chromatin proteins, determine the “epigenome chaos”, which means that the changes of epigenetic traits are randomly generated, but strongly selected by deterministic events. Disordered changes of DNA methylation profiles are the hallmarks of all cancer types, but it is not clear if aberrant methylation is the cause or the consequence of cancer evolution. Critical points to address are the profound epigenetic intra- and inter-tumor heterogeneity and the nature of the heterogeneity of the methylation patterns in each single cell in the tumor population. To analyze the methylation heterogeneity of tumors, new technological and informatic tools have been developed. This review discusses the state of the art of DNA methylation analysis and new approaches to reduce or solve the complexity of methylated alleles in DNA or cell populations.

scholarly journals A novel reannotation strategy for dissecting DNA methylation patterns of human long intergenic non-coding RNAs in cancers

2014 ◽  
Vol 42 (13) ◽  
pp. 8258-8270 ◽  
Author(s):  
Hui Zhi ◽  
Shangwei Ning ◽  
Xiang Li ◽  
Yuyun Li ◽  
Wei Wu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Non Coding Rnas ◽  
Methylation Patterns

Heterogeneity and Evolution Of DNA Methylation In Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1626-1626
Author(s):  
Christopher C Oakes ◽  
Rainer Claus ◽  
Lei Gu ◽  
Yassen Assenov ◽  
Jennifer Hüllein ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Research Funding ◽  
Tumor Heterogeneity ◽  
Time Window ◽  
Lymphocytic Leukemia ◽  
Epigenetic Alterations ◽  
Genetic Aberrations ◽  
Time Points ◽  
Methylation Patterns ◽  
Selection Of

Abstract Evolution and resulting tumor heterogeneity is currently under investigation for many malignancies since it may explain resistance of tumors to therapies. Pronounced intra-tumor genetic variation has been recently appreciated for solid tumors and leukemias, including chronic lymphocytic leukemia (CLL). Heterogeneous epigenetic alterations, such as DNA methylation, have the potential to add complexity to the leukemic cell population. Studies of the CLL methylome have revealed an abundance of genomic loci that display altered DNA methylation states, including methylation marks showing high prognostic significance. Despite the ubiquity of these epigenetic alterations, the mechanisms and impact of changes to the tumor epigenome in CLL are currently undefined. Here, we have used Illumina 450k arrays and next-generation sequencing to evaluate intra-tumor heterogeneity and evolution of DNA methylation and genetic aberrations in 80 cases of CLL, with 30 cases evaluated at two or more time points. CLL cases exhibit vast inter-patient differences in intra-tumor methylation heterogeneity. Genetically clonal cases maintain low methylation heterogeneity, resulting in up to 10% of total CpGs existing in a monoallelically-methylated state throughout the tumor cell population. Cases with high levels of methylation heterogeneity display a significantly shorter treatment-free time window preceding first therapy (median difference 11 vs. 49 months, P<0.01), coincident with unfavorable prognostic markers (IGHV unmutated, P<0.01; ZAP70 demethylated, P<0.05). Increasing methylation heterogeneity correlates with advanced genetic subclonal complexity (P<0.001). Intriguingly, a longitudinal evaluation reveals that selection of novel global DNA methylation patterns is observed only in cases that undergo genetic evolution. The level of methylation heterogeneity and presence of a genetic subclonal driver mutation in early time points are significantly associated with methylation evolution, signifying that heterogeneity indicates the presence of active evolution occurring within the tumor population. Independent genetic evolution without broad alterations to DNA methylation is uncommon and is associated with low-risk genetic alterations (e.g. deletion of 13q14). Cases showing high levels of methylation evolution display a significantly shorter event-free time window following first therapy (median survival 9 vs. 110 months, P<0.0001). This study articulates the novel finding of epigenetic and genetic coevolution in leukemia and highlights the dominant role of genetic aberrations in the selection of developing methylation patterns. As epigenetics plays a key role in determining cellular phenotypes, we propose that parallel alterations to the genome and epigenome endow expanding subclonal leukemic populations with novel attributes which contribute to acquired therapy resistance. This work also advocates a benefit of monitoring DNA methylation heterogeneity and evolution during CLL disease course. Disclosures: Kipps: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding.

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