scholarly journals A Global Gene Body Methylation Measure Correlates Independently with Overall Survival in Solid Cancer Types

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2257
Author(s):  
Dietmar Pils ◽  
Elisabeth Steindl ◽  
Anna Bachmayr-Heyda ◽  
Sabine Dekan ◽  
Stefanie Aust
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Overall Survival ◽  
Cancer Biology ◽  
Methylation Status ◽  
Cpg Methylation ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Genome Wide ◽  
Cancer Types

Epigenetics, CpG methylation of CpG islands (CGI) and gene bodies (GBs), plays an important role in gene regulation and cancer biology, the former established as a transcription regulator. Genome wide CpG methylation, summarized over GBs and CGIs, was analyzed for impact on overall survival (OS) in cancer. The averaged GB and CGI methylation status of each gene was categorized into methylated and unmethylated (defined) or undefined. Differentially methylated GBs and genes associated with their GB methylation status were compared to the corresponding CGI methylation states and biologically annotated. No relevant correlations of GB and CGI methylation or GB methylation and gene expression were observed. Summarized GB methylation showed impact on OS in ovarian, breast, colorectal, and pancreatic cancer, and glioblastoma, but not in lung cancer. In ovarian, breast, and colorectal cancer more defined GBs correlated with unfavorable OS, in pancreatic cancer with favorable OS and in glioblastoma more methylated GBs correlated with unfavorable OS. The GB methylation of genes were similar over different samples and even over cancer types; nevertheless, the clustering of different cancers was possible. Gene expression differences associated with summarized GB methylation were cancer specific. A genome-wide dysregulation of gene-body methylation showed impact on the outcome in different cancers.

scholarly journals Phylogenetic Shifts in Gene Body Methylation Correlate with Gene Expression and Reflect Trait Conservation

2019 ◽  
Vol 37 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Danelle K Seymour ◽  
Brandon S Gaut
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Molecular Evolution ◽  
Methylation Status ◽  
Evolutionary Constraint ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Plant Genomes ◽  
Genome Wide ◽  
Rates Of Molecular Evolution

Abstract A subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.

scholarly journals Phylogenetic shifts in gene body methylation correlate with gene expression and reflect trait conservation

2019 ◽  
Author(s):  
Danelle K. Seymour ◽  
Brandon S. Gaut
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Molecular Evolution ◽  
Methylation Status ◽  
Evolutionary Constraint ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Plant Genomes ◽  
Genome Wide ◽  
Rates Of Molecular Evolution

ABSTRACTA subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.

scholarly journals LPS-induced expression of CD14 in the TRIF pathway is epigenetically regulated by sulforaphane in porcine pulmonary alveolar macrophages

2016 ◽  
Vol 22 (8) ◽  
pp. 682-695 ◽  
Author(s):  
Qin Yang ◽  
Maren J Pröll ◽  
Dessie Salilew-Wondim ◽  
Rui Zhang ◽  
Dawit Tesfaye ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alveolar Macrophages ◽  
Methylation Status ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Tnf Α ◽  
Pulmonary Alveolar Macrophages ◽  
Cluster Of Differentiation ◽  
Cd14 Gene

Pulmonary alveolar macrophages (AMs) are important in defense against bacterial lung inflammation. Cluster of differentiation 14 (CD14) is involved in recognizing bacterial lipopolysaccharide (LPS) through MyD88-dependent and TRIF pathways of innate immunity. Sulforaphane (SFN) shows anti-inflammatory activity and suppresses DNA methylation. To identify CD14 epigenetic changes by SFN in the LPS-induced TRIF pathway, an AMs model was investigated in vitro. CD14 gene expression was induced by 5 µg/ml LPS at the time point of 12 h and suppressed by 5 µM SFN. After 12 h of LPS stimulation, gene expression was significantly up-regulated, including TRIF, TRAF6, NF-κB, TRAF3, IRF7, TNF-α, IL-1β, IL-6, and IFN-β. LPS-induced TRAM, TRIF, RIPK1, TRAF3, TNF-α, IL-1β and IFN-β were suppressed by 5 µM SFN. Similarly, DNMT3a expression was increased by LPS but significantly down-regulated by 5 µM SFN. It showed positive correlation of CD14 gene body methylation with in LPS-stimulated AMs, and this methylation status was inhibited by SFN. This study suggests that SFN suppresses CD14 activation in bacterial inflammation through epigenetic regulation of CD14 gene body methylation associated with DNMT3a. The results provide insights into SFN-mediated epigenetic down-regulation of CD14 in LPS-induced TRIF pathway inflammation and may lead to new methods for controlling LPS-induced inflammation in pigs.

Shared DNA-based copy number with divided methylation changes differentiate and clinically associate early stage pancreatic cancer tumors.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 434-434
Author(s):  
Eva Chao ◽  
Kyaw Lwin Aung ◽  
Qi Xu ◽  
William H. Matsui ◽  
Jeanne Kowalski
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Overall Survival ◽  
Clinical Outcomes ◽  
Copy Number ◽  
Cancer Biology ◽  
Early Stage ◽  
Molecular Taxonomy ◽  
Unmet Need ◽  
Gene Copy

434 Background: There is no known molecular taxonomy of pancreatic cancer that can guide therapeutic strategies. Understanding the fundamental molecular mechanism underlying pancreatic cancer biology remains an unmet need. We explore the extent to which combinations of DNA-based molecular changes in copy number (CN) and methylation separate early stage PAAD tumors and associated with survival outcomes. Methods: We performed genome-wide combined cluster analyses on DNA-based CN and methylation changes using TCGA data. We examined cluster associations with clinical outcomes by comparing in months (mos), Kaplan--Meier estimated overall survival (OS) and disease-free interval (DFI) using a log-rank test. We performed additional comparisons among CN-Methylation derived clusters with respect to PAAD phenotypes. Results: Using 78 early stage pancreatic cancer tumors from TCGA with CN, methylation and clinical outcomes data, we identified two patient clusters with distinct gene copy number signatures that when combined with three methylation signatures, resulted in three additional clusters. Thus, the same gene CN signature, when combined with different methylation signatures, further differentiated tumors into sub-clusters with varying levels of associations with clinical outcome. Among them, analogous to current gene-expression based subtypes, we also identified an immune-rich subtype that was associated with improved overall survival (n=21, median OS=16mos; DFI=16mos), and an extracellular matrix (ECM)-rich with worse survival (n=19, median OS=12mos; DFI=8mos). Unlike previous expression subtypes, we identified another metabolic-enriched subtype with the same worse median OS and DFI, differentiated by methylation with the ECM-rich subtype. The improved OS cluster had a signature of CN neutral and increased methylation, while the poor cluster had a signature of CN gains and increased methylation among a set of genes distinct from the improved cluster. No significant differences in age, site, microsatellite instability and KRAS status among clusters were noted. Notably, in a multivariable model that included gene expression-based subtypes, only our DNA-level subtypes remained significantly associated with overall survival. Conclusions: While RNA-level changes often display large variations, DNA-level changes are more robust. Copy number changes appear to separate tumors into poor and improved prognosis clusters, while methylation appears to inform on the further separation of poor prognosis into various levels. A DNA-based molecular taxonomy for early stage pancreatic cancer could prove invaluable when used in combination with methylation-based circulating tumor DNA assays for clinical trial monitoring of tumor responses.

scholarly journals Role of gene body methylation in coral acclimatization and adaptation

2017 ◽  
Author(s):  
Groves Dixon ◽  
Yi Liao ◽  
Line K. Bay ◽  
Mikhail V. Matz
Keyword(s):  
Gene Expression ◽  
Housekeeping Genes ◽  
Gene Body ◽  
Transgenerational Inheritance ◽  
Gene Body Methylation ◽  
Transgenerational Plasticity ◽  
Genome Wide ◽  
Environmentally Responsive ◽  
Predict Gene Expression

AbstractGene body methylation (GBM) has been hypothesized to modulate responses to environmental change, including transgenerational plasticity, but the evidence thus far has been lacking. Here we show that coral fragments reciprocally transplanted between two distant reefs respond with genome-wide increase or decrease in GBM disparity among genes. Surprisingly, this simple genome-wide adjustment predicted broad-scale gene expression changes and fragments’ fitness in the new environment. This supports GBM’s role in acclimatization, which may consist in modulating the expression balance between environmentally-responsive and housekeeping genes. At the same time, constitutive differences in GBM between populations did not align with plastic GBM changes upon transplantation and were mostly observed amongFSToutliers, indicating that they arose through genetic divergence rather than through transgenerational inheritance of acquired GBM states.One-sentence summaryGenome-wide shifts in gene body methylation predict gene expression and fitness during acclimatization but do not contribute to epigenetic divergence between populations.

MGMT Epigenetics: The Influence of Gene Body Methylation and other Insights Derived from Integrated Methylomic, Transcriptomic, and Chromatin Analyses for Various Cancer Types

2021 ◽  
Vol 21 ◽  
Author(s):  
Manny D. Bacolod ◽  
Francis Barany
Keyword(s):  
Cell Lines ◽  
Promoter Region ◽  
Dna Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Cpg Methylation ◽  
Open Chromatin ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Cpg Sites ◽  
Cancer Types

Background: MGMT (O6-methylguanine-DNA methyltransferase) is primarily responsible for limiting the activity of some widely used chemotherapeutic agents, including temozolomide (TMZ) and carmustine (BCNU). The gene encoding this protein is epigenetically regulated, and assessment of methylation at its promoter region is used to predict glioma patients’ response to TMZ. Methods: In this report, we employed a bioinformatic approach to elucidate MGMT’s epigenetic regulation. Integrated for the analysis were genome-wide methylation and transcription datasets for > 8,600 human tissue (representing 31 distinct cancer types ) and 500 human cancer cell line samples. Also crucial to the interpretation of results were publicly available data from the ENCODE Project: tracks for histone modifications (via ChIP-seq) and DNase I hypersensitivity (via DNaseseq), as well as methylation and transcription data for representative cell lines (HeLa-S3, HMEC, K562). Results and discussion: We were able to validate (perhaps more comprehensively) the contrasting influences of CpG methylation at promoter region and at gene body on MGMT transcription. While the MGMT promoter is populated by CpG sites whose methylation levels displayed high negative correlation (R) with MGMT mRNA counts, the gene body harbors CpG sites exhibiting high positive R values. The promoter CpG sites with very high negative R’s across cancer types include cg12981137, cg12434587, and cg00618725. Among the notable gene body CpG sites (high positive R’s across cancer types) are cg00198994 (Intron 1), cg04473030 (Intron 2), and cg07367735 (Intron 4). For certain cancer types, such as melanoma, gene body methylation appears to be a better predictor of MGMT transcription (compared to promoter methylation). In general, the CpG methylation v. MGMT expression R values are higher in cell lines relative to tissues. Also, these correlations are noticeably more prominent in certain cancer types such as colorectal, adrenocortical, esophageal, skin, and head and neck cancers, as well as glioblastoma. Conclusion: As expected, hypomethylation at the promoter region is associated with more open chromatin, and enrichment of histone marks H3K4m1, H3K4m2, H3K4m3, and H3K9ac. The observations reported here may be useful in improving diagnostic assays for MGMT.

scholarly journals On the origin and evolutionary consequences of gene body DNA methylation

2016 ◽  
Vol 113 (32) ◽  
pp. 9111-9116 ◽  
Author(s):  
Adam J. Bewick ◽  
Lexiang Ji ◽  
Chad E. Niederhuth ◽  
Eva-Maria Willing ◽  
Brigitte T. Hofmeister ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Recombinant Inbred Lines ◽  
Dna Methyltransferases ◽  
Inbred Lines ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Eutrema Salsugineum ◽  
And Function ◽  
Evolutionary Consequences

In plants, CG DNA methylation is prevalent in the transcribed regions of many constitutively expressed genes (gene body methylation; gbM), but the origin and function of gbM remain unknown. Here we report the discovery that Eutrema salsugineum has lost gbM from its genome, to our knowledge the first instance for an angiosperm. Of all known DNA methyltransferases, only CHROMOMETHYLASE 3 (CMT3) is missing from E. salsugineum. Identification of an additional angiosperm, Conringia planisiliqua, which independently lost CMT3 and gbM, supports that CMT3 is required for the establishment of gbM. Detailed analyses of gene expression, the histone variant H2A.Z, and various histone modifications in E. salsugineum and in Arabidopsis thaliana epigenetic recombinant inbred lines found no evidence in support of any role for gbM in regulating transcription or affecting the composition and modification of chromatin over evolutionary timescales.

Abstract 40: Disturbed Flow Alters Genomewide DNA Methylation Patterns, Regulating Endothelial Gene Expression and Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jessilyn Dunn ◽  
Haiwei Qiu ◽  
Soyeon Kim ◽  
Daudi Jjingo ◽  
Ryan Hoffman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Western Diet ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Endothelial Gene Expression

Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. We found that d-flow induced expression of DNMT1, but not DNMT3a or DNMT3b, in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) compared to unidirectional laminar shear in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two atherosclerosis models using ApoE-/- mice (western diet for 3 months and the partial carotid ligation model with western diet for 3 weeks). To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and transcript microarray using endothelial-enriched gDNA and RNA, respectively, obtained from the partially-ligated left common carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA exposed to s-flow) of mice treated with 5Aza or vehicle. D-flow induced DNA hypermethylation in 421 gene promoters, which was significantly prevented by 5Aza in 335 genes. Systems biological analyses using the RRBS and the transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated by d-flow but rescued by 5Aza treatment. Of those, five genes contain hypermethylated cAMP-response-elements in their promoters, including the transcription factors HoxA5 and Klf3. Their methylation status could serve as a mechanosensitive master switch in endothelial gene expression. Our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

scholarly journals Gene body methylation mediates epigenetic inheritance of plant traits

2021 ◽  
Author(s):  
Zaigham Shahzad ◽  
Jonathan D. Moore ◽  
Daniel Zilberman
Keyword(s):  
Gene Expression ◽  
Flowering Time ◽  
Cytosine Methylation ◽  
Plant Traits ◽  
Phenotypic Diversity ◽  
Strong Association ◽  
Epigenetic Inheritance ◽  
Evolutionary Significance ◽  
Gene Body ◽  
Gene Body Methylation

AbstractCytosine methylation is an epigenetically heritable DNA modification common in plant and animal genes, but the functional and evolutionary significance of gene body methylation (gbM) has remained enigmatic. Here we show that gbM enhances gene expression in Arabidopsis thaliana. We also demonstrate that natural gbM variation influences drought and heat tolerance and flowering time by modulating gene expression, including that of Flowering Locus C (FLC). Notably, epigenetic variation accounts for as much trait heritability in natural populations as DNA sequence polymorphism. Furthermore, we identify gbM variation in numerous genes associated with environmental variables, including a strong association between flowering time, spring atmospheric NO2 – a by-product of fossil fuel burning – and FLC epialleles. Our study demonstrates that gbM is an important modulator of gene expression, and its natural variation fundamentally shapes phenotypic diversity in plant populations. Thus, gbM provides an epigenetic basis for adaptive evolution independent of genetic polymorphism.

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