scholarly journals Genome-wide DNA methylation patterns reveal clinically relevant predictive and prognostic subtypes in osteosarcoma

2020 ◽  
Author(s):  
Christopher E. Lietz ◽  
Erik T. Newman ◽  
Andrew D. Kelly ◽  
Santiago A. Lozano-Calderon ◽  
David H. Ebb ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Methylation Pattern ◽  
Transcriptional Analysis ◽  
Chemotherapy Response ◽  
Methylation Array ◽  
Genome Wide ◽  
Recurrent Mutations ◽  
Methylation Patterns ◽  
Genomic Methylation

ABSTRACTBackgroundOsteosarcoma (OSA) is an aggressive malignancy predominantly affecting children and young-adults. Genetic analysis has characterized very few recurrent mutations in OSA, and an improved understanding of interpatient tumor heterogeneity is needed for clinical management.MethodsWe analyzed genome-wide DNA methylation in primary OSA tumors from the NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n = 83) profiled using the Illumina 450K methylation array. We tested if broad genomic methylation predicted outcomes and defined supervised methylomic signatures predictive of Recurrence Free Survival (RFS), Chemotherapy Response (CR), and Metastatic disease at Diagnosis (MetDx). We assessed methylation pattern reproducibility in two independent clinical datasets (n = 28 and 34) and in an in vitro dataset (n = 11). Correlations between genomic methylation and transcription were tested using TARGET RNA-seq data. An in silico pharmacogenomic screen was performed to identify agents for future stratified application.ResultsGenome-wide methylation defined two subgroups. Relatively hypomethylated tumors experienced better chemotherapy response (Odds Ratio = 6.429, Fisher’s p = 0.007), longer RFS (metastatic, median 2.3 vs 26.7 months, localized, median 63.5 vs 104.7 months, stratified log-rank p = 0.006), and Overall Survival (p = 5×10-4) than hypermethylated tumors. Robust genomic methylation signatures predictive of RFS and CR were defined, and the signatures’ methylation patterns were reproducible in the independent clinical and in vitro datasets. The RFS signature was enriched for intragenic sites, whereas the CR signature and clinically relevant genome-wide methylation patterns were enriched for intergenic sites. Normal-tissue-like methylation patterns were associated with poor prognosis and in vitro analysis suggested that the methylation signatures are associated with tumor aggressiveness. Downstream transcriptional analysis revealed that genes annotated to the RFS methylation signature were also predictive survival. The transcriptional program represented in the RFS signature included several critical cellular pathways, whereas the CR signature was associated with much fewer known pathways, possibly reflecting a much broader cellular “methylation state” related to chemoresponse. A pharmacogenomic screen identified potential therapies, including epigenomic modifiers, for future stratified clinical application.ConclusionGenomic methylation offers insight into patient prognosis and could be a useful tool for developing alternate adjuvant therapeutic strategies.

scholarly journals Influence of Mouse-Strain-Specific Factors on Position-Dependent Transgene DNA Methylation Patterns

1996 ◽  
Vol 45 (1-2) ◽  
pp. 243-244
Author(s):  
P.A. Koetsier ◽  
W. Doerfler
Keyword(s):  
Dna Methylation ◽  
Genetic Background ◽  
Promoter Activity ◽  
Blot Hybridization ◽  
Southern Blot Hybridization ◽  
Adenovirus Type ◽  
Methylation Pattern ◽  
Parent Of Origin ◽  
Methylation Patterns

In previous work from this laboratory, an inverse dependence was established for the adenovirus type 2 E2A late promoter between sequence-specific DNA methylation and promoter activity [1-5; for reviews see ref. 6, 7]. The effect of DNA methylation on promoter activity was also assessed in the transgenic mice, which were obtained from microinjections of unmethylated or in vitro HpaII-premethylated pAd2E2AL-CAT DNA [1] into F2 zygotes from B6D2F, (C57BL/6 × DBA/2) hybrid mice. In CAT assays carried out on organ extracts from the pAd2E2AL-CAT mice, the inverse relationship was confirmed [2].We studied the stability of the pAd2E2AL-CAT DNA methylation patterns in up to eight mouse generations and assessed the influence of the strain-specific genetic background. Three pAd2E2AL-CAT mouse lines were crossed with inbred DBA/2, C57BL/6 or B6D2F, mice. Parent-of-origin effects were controlled by exclusive hemizygous transgene transmission either via females or males. The founder animal of line 7-1 carried two groups of transgenes (A and B) on separate chromosomes. The transgene methylation patterns of the 7-1B transgenes and those of the lines 5-8 and 8-1 were stably transmitted.Southern blot hybridization experiments [8, 9] revealed that the 7-1A transgene methylation pattern was a cellular mosaic. In mixed-genetic-background offspring from 7-1A animals, 10% carried transgenes with HpaII-DNA methylation levels that were reduced from 40 to 10-15%. This finding suggested that in this background the factors that supported high methylation levels were dominant. When inbred DBA/2 mice were the mates, 40% of the siblings carried demethylated transgenes, whereas this ratio amounted to only 10% in C57BL/6 offspring (comparable to B6D2F1 crossings). Transgene methylation patterns were not detectably influenced by the parent-of-origin.

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 Genome-Wide DNA Methylation Patterns of Bovine Blastocysts Developed In Vivo from Embryos Completed Different Stages of Development In Vitro

PLoS ONE ◽  
2015 ◽  
Vol 10 (11) ◽  
pp. e0140467 ◽  
Author(s):  
Dessie Salilew-Wondim ◽  
Eric Fournier ◽  
Michael Hoelker ◽  
Mohammed Saeed-Zidane ◽  
Ernst Tholen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stages Of Development ◽  
Genome Wide ◽  
Development In Vitro ◽  
Methylation Patterns

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.

Zika Virus Changes Methylation of Genes Involved in Immune Response and Neural Development in Brazilian Babies Born With Congenital Microcephaly

2020 ◽  
Author(s):  
Denise Anderson ◽  
João I C F Neri ◽  
Cássio R M Souza ◽  
Joanna G Valverde ◽  
Josélio M G De Araújo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Neural Development ◽  
Zika Virus ◽  
Clinical Signs ◽  
Genome Wide ◽  
Immunity Genes ◽  
Congenital Microcephaly ◽  
Methylation Patterns ◽  
Methylation Profiling

Abstract The recent increase in babies born with brain and eye malformations in Brazil is associated with Zika virus (ZIKV) infection in utero. ZIKV alters host DNA methylation in vitro. Using genome-wide DNA methylation profiling we compared 18 babies born with congenital ZIKV microcephaly with 20 controls. We found ZIKV-associated alteration of host methylation patterns, notably at RABGAP1L which is important in brain development, at viral host immunity genes MX1 and ISG15, and in an epigenetic module containing the causal microcephaly gene MCPH1. Our data support the hypothesis that clinical signs of congenital ZIKV are associated with changes in DNA methylation.

scholarly journals Human blood DNA methylation patterns reflect individual lifestyle

2021 ◽  
Author(s):  
Ireen Klemp ◽  
Anne Hoffmann ◽  
Luise Mueller ◽  
Tobias Hagemann ◽  
Kathrin Horn ◽  
...  
Keyword(s):  
Physical Activity ◽  
Dna Methylation ◽  
Population Based ◽  
Methylation Pattern ◽  
Unhealthy Lifestyle ◽  
Genome Wide ◽  
Intersection Analysis ◽  
Methylation Patterns ◽  
Dna Methylation Analysis ◽  
Modifiable Lifestyle Factors

Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects (diet, physical activity, smoking and alcohol) on blood DNA methylation in participants of the LIFE-Adult study, a well-characterized population-based cohort from Germany. Fifty subjects with an extremely healthy and 50 with an extremely unhealthy lifestyle were selected for genome-wide DNA methylation analysis in blood samples. Whereas obesity was only marginally related to variability in DNA methylation pattern, comparisons between lifestyle categories resulted in 145 Differentially Methylated Positions (DMPs) and 4682 Differentially Methylated Regions (DMRs) annotated to 4426 unique genes. Intersection analysis showed that diet, physical activity, smoking and alcohol intake are equally contributing to the observed differences, which particularly affects pathways related to glutamatergic synapse and axon guidance. DNA methylation patterns help discriminate individuals with a healthy vs. unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.

Genome-Wide DNA Methylation Analysis of Patients with Myelodysplastic Syndrome After Azacitidine Treatment.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 600-600
Author(s):  
Hyang-Min Byun ◽  
Timothy Triche ◽  
Hyeoung-Joon Kim ◽  
Hee Nam Kim ◽  
Yeo-Kyeoung Kim ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
Who Classification ◽  
Methylation Pattern ◽  
Methylation Analysis ◽  
Cpg Sites ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Dna Methylation Analysis ◽  
Hypermethylated Genes

Abstract Abstract 600 Background: Azacitidine is hypothesized to exert its therapeutic effect in patients with myelodysplastic syndrome (MDS) through inhibition of DNA methylation. However to date no genomic DNA methylation pattern has been shown to predict response to azacitidine in patients with MDS, and no aberrantly silenced gene or group of genes has been shown to be reactivated by azacitidine that can be clearly linked to the beneficial clinical effect. We sought to identify the gene or group of aberrantly hypermethylated genes that are responsible for the therapeutic effect of azacitidine by retrospectively analyzing genome-wide DNA methylation profiles from bone marrow samples of a cohort of 113 patients with MDS treated with the DNA methylation inhibitor, azacitidine. Methods: Bone marrow aspirates were collected at time of diagnosis prior to treatment, after 4 cycles of azacitidine therapy and 8 cycles of therapy. DNA was isolated and bisulfite treated with the EZ-96 DNA Methylation-Gold Kit. DNA methylation analysis was performed on 27,578 CpG sites representing 14,475 genes (almost ¾ of known genes) using the Infinium Bead Array system for samples at the time of diagnosis, 4 and 8 cycles of therapy. Only 19,662 CpG sites were used for further analysis due to exclusion of CpG sites that were on the × chromosome, sites suspected of containing single nucleotide polymorphisms (SNP), and sites within DNA repeats. In total 91 samples were analyzed from 43 patients with MDS, which were selected to represent different disease classifications and responses to therapy, and bone marrow aspirates from 10 healthy control subjects without MDS. Results: Two-way hierarchical cluster analysis showed clear clustering of bone marrow samples taken from subjects without MDS. DNA methylation patterns from healthy controls clustered together, and pre and post azacitidine treatment samples from the same subject clustered together as well. Samples did not cluster by DNA methylation patterns for WHO classification, International Prognostic Scoring System (IPSS), cytogenetic abnormalities, or response to azacitidine. Supervised cluster analysis is ongoing. Global decreases in DNA methylation as measured by the average methylation for all 19,662 loci assayed did decrease with treatment and there was a trend for a larger decrease in DNA methylation in those patients who responded to azacitidine. Conclusion: In this pilot study of genome-wide DNA methylation analysis of MDS patients treated with azacitidine we find global decreases of DNA methylation. We were unable to identify a DNA methylation pattern or group of hypermethylated genes that would predict response to azacitidine. MDS samples did not cluster by WHO classification, IPSS or response to azacitidine. Larger translational studies are needed, but the possibility that DNA methylation decreases in patients treated with azacitidine serve as a pharmacological marker rather than a therapeutic target should also be considered Disclosures: Laird: Celgene: Consultancy. Yang:Celgene: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Sexually divergent DNA methylation programs with hippocampal aging

2017 ◽  
Author(s):  
Dustin R. Masser ◽  
Niran Hadad ◽  
Hunter Porter ◽  
Colleen A. Mangold ◽  
Archana Unnikrishnan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sex Differences ◽  
Biological Aging ◽  
Age Related ◽  
Genome Wide ◽  
Aging Response ◽  
Genomic Location ◽  
Methylation Patterns ◽  
Genomic Methylation

SummaryDNA methylation is a central regulator of genome function and altered methylation patterns are indicative of biological aging and mortality. Age-related cellular, biochemical, and molecular changes in the hippocampus lead to cognitive impairments and greater vulnerability to neurodegenerative disease that varies between the sexes. The role of hippocampal epigenomic changes with aging in these processes is unknown as no genome-wide analyses of age-related methylation changes have considered the factor of sex in a controlled animal model. High-depth, genome-wide bisulfite sequencing of young (3 month) and old (24 month) male and female mouse hippocampus revealed that while total genomic methylation amounts did not change with aging, specific sites in CG and non-CG (CH) contexts demonstrated age-related increases or decreases in methylation that were predominantly sexually divergent. Differential methylation with age for both CG and CH sites was enriched in intergenic, and intronic regions and under-represented in promoters, CG islands and specific enhancer regions in both sexes suggesting that certain genomic elements are especially labile with aging, even if the exact genomic loci altered are predominantly sex-specific. Life-long sex differences in autosomal methylation at CG and CH sites were also observed. The lack of genome-wide hypomethylation, sexually divergent aging response, and autosomal sex differences at CG sites were confirmed in human data. These data reveal sex as a previously unappreciated central factor of hippocampal epigenomic changes with aging. In total, these data demonstrate an intricate regulation of DNA methylation with aging by sex, cytosine context, genomic location, and methylation level.

scholarly journals TANC1 methylation as a novel biomarker for the diagnosis of patients with anti-tuberculosis drug-induced liver injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dongxue Wu ◽  
Yuhong Li ◽  
Qi Ren ◽  
Shengfei Pei ◽  
Lin Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Peripheral Blood ◽  
Target Genes ◽  
Characteristic Analysis ◽  
Drug Induced ◽  
Blood Samples ◽  
Cpg Sites ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Genomic Methylation

AbstractWe aimed to elucidate the differences in genomic methylation patterns between ADLI and non-ADLI patients to identify DNA methylation-based biomarkers. Genome-wide DNA methylation patterns were obtained using Infinium MethylationEPIC (EPIC) BeadChip array to analyze 14 peripheral blood samples (7 ADLI cases, 7 non-ADLI controls). Changes in the mRNA and DNA methylation in the target genes of another 120 peripheral blood samples (60 ADLI cases, 60 non-ADLI controls) were analyzed by real-time polymerase chain reaction and pyrosequencing, respectively. A total of 308 hypermethylated CpG sites and 498 hypomethylated CpG sites were identified. Significantly, hypermethylated CpG sites cg06961147 and cg24666046 in TANC1 associated with ADLI was identified by genome-wide DNA methylation profiling. The mRNA expression of TANC1 was lower in the cases compared to the controls. Pyrosequencing validated these two differentially methylated loci, which was consistent with the results from the EPIC BeadChip array. Receiver operating characteristic analysis indicated that the area under the curve of TANC1 (cg06961147, cg24666046, and their combinations) was 0.812, 0.842, and 0.857, respectively. These results indicate that patients with ADLI have different genomic methylation patterns than patients without ADLI. The hypermethylated differentially methylated site cg06961147 combined with cg24666046 in TANC1 provides evidence for the diagnosis of ADLI.

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