Supplementary Table from Global DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast Cancer Stroma
Coral HalperinJoschka HeyDieter WeichenhanYaniv SteinShimrit MayerPavlo LutsikChristoph PlassRuth Scherz‐Shouval
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Supplementary Table from Global DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast Cancer StromaKeywords:
RUNX1
Epigenetic mechanisms are known to be involved in tissue-specific differentiation. DNA methylation patterns have been shown to be largely conserved across tissues but with variation for specific genes. However, it is unclear whether the variability observed in the methylation profile of a metabolically active tissue is reflected in other sources such as hematopoietic tissue. This study aimed to test blood genome-wide CpG site methylation levels as a surrogate model for visceral adipose tissue (VAT) methylation and to verify whether it appropriately reflects differences in methylation levels found in VAT between men discordant for the metabolic syndrome (MetS). Tissue specimens (VAT and blood samples) were obtained from 16 severely obese individuals discordant for the MetS. CpG sites methylation levels were measured with the Infinium HumanMethylation450 BeadChip and correlations of methylation levels between VAT and blood were computed. Differences in methylation levels between individuals with and without MetS were tested in both tissues. Pathway analysis was conducted for differentially methylated CpG sites common to both tissues. High cross-tissue correlations were observed for VAT and blood (0.952±0.014) while some CpG sites had significantly different methylation levels in VAT versus blood. Differential methylation analysis between individuals with and without MetS demonstrated a higher number of differentially methylated CpG sites in VAT than in blood (11,778 vs. 881, respectively) with nearly 4% of differentially methylated sites found in VAT being also represented in blood. Common differentially methylated sites were involved in inflammatory-, lipid- and diabetes-related pathways. These results suggest that blood methylation levels of specific CpG sites may adequately reflect VAT methylation levels for some of the MetS-related genes, specifically for inflammatory, lipid and glucose metabolism genes.
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Abstract We report that the DNA methylation profile of a child’s neonatal whole blood can be significantly influenced by his or her mother’s neonatal blood lead levels (BLL). We recruited 35 mother-infant pairs in Detroit and measured the whole blood lead (Pb) levels and DNA methylation levels at over 450,000 loci from current blood and neonatal blood from both the mother and the child. We found that mothers with high neonatal BLL correlate with altered DNA methylation at 564 loci in their children’s neonatal blood. Our results suggest that Pb exposure during pregnancy affects the DNA methylation status of the fetal germ cells, which leads to altered DNA methylation in grandchildren’s neonatal dried blood spots. This is the first demonstration that an environmental exposure in pregnant mothers can have an epigenetic effect on the DNA methylation pattern in the grandchildren.
Blood lead level
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CpG site
Pathogenesis
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Introduction and Aim: The DNA methylation is involved in the regulation of gene activity and abnormal DNA methylation is associated with various diseases, including cancer. MAP9 (Microtubule-Associated Protein 9) gene methylation was investigated as a potential epigenetic biomarker for cancer in this work. The results were published in Cancer Research. Materials and Methods: The present study was on 40 breast cancer samples and 20 healthy samples to identify diagnosis biomarkers for breast cancer. DNA was extracted from the whole blood of breast cancer patients and healthy samples and were converted to bisulfite by using EpiTect Fast DNA Bisulfite Kit –Part 1 from Qiagen company. Then used Qia gene methylation kit to identify methylated site an epigenetic marker (MAP9) using HRM software in RT-PCR. Results: The findings of the present investigation revealed that the methylation of the MAP9 gene in breast cancer patients were 28 (70%) compared to healthy patients 2 (10%) at a significant difference (P<0.01). Conclusion: The MAP9 gene is hypermethylated in breast cancer patients, and it has the potential to be exploited as a molecular biomarker for the detection of breast cancer.
Bisulfite sequencing
Bisulfite
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The 'Fuji' line includes many varieties with a similar genetic background and consistent inducement factors with epigenetic occurrence, thus it may be considered an ideal candidate for epigenetic research. In this study, 91 bud mutations of 'Fuji' apple were used as the test materials. Using the genetic variation within 'Fuji' as the control, the characteristics of epigenetic variation at different levels in both varieties and mutant groups were examined. The results showed that: (1) the global genomic DNA methylation level of the 91 bud mutants of 'Fuji' ranged from 29.120%-45.084%, with an average of 35.910%. Internal cytosine methylation was the main DNA methylation pattern. Regarding the variation of methylation patterns of 'Fuji' mutants, the vast majority of loci maintained the original methylation pattern existed in 'Fuji'. CHG methylation variation was the main type of variation; (2) the variation in methylation patterns between the mutant groups was greater than that of methylation levels. Among these patterns, the variation in CHG methylation patterns (including CHG hypermethylation and CHG demethylation) was expected to be dominant. The observed variation in methylation levels was more important in the Color mutant group; however, the variation in methylation patterns was more obvious in both the early maturation and Spur mutant groups. Moreover, the range of variation in the Early-maturation group was much wider than that in the Spur mutant group; (3) epigenetic diversity and genetic diversity were both low between the mutant groups. In the 'Fuji' mutant groups, there was few correlation between genetic and epigenetic variation, and epigenetic differentiation resulted in more loci with moderate or greater differentiation; (4) the purifying selection seemed to play a major role in the differentiation of different groups of 'Fuji' mutants (65.618%), but epigenetic diversity selection still occurred at nearly 35% of loci. Sixteen epigenetic outlier loci were detected.
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Dinoflagellate
Epigenesis
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Background: MDS is a heterogeneous group of myeloid neoplasms caused by genetic and epigenetic alterations. While the major driver mutations in MDS have been fully investigated, the role of epigenetic alterations, particularly those of DNA methylation, has less intensively been studied. Aims: To clarify the role of epigenetic aberrations in the pathogenesis of MDS. Methods: We analyzed DNA methylation status of bone marrow mononuclear cells from 320 cases with MDS‐SLD ( n = 7), MDS‐RS ( n = 63), MDS‐MLD ( n = 51), MDS‐EB ( n = 186), MDS‐U ( n = 1), and MDS with isolated del(5q) ( n = 12), using Illumina 450K methylation array. Mutations in major driver genes (51 genes) were also interrogated using targeted‐capture sequencing. Results: Using unsupervised consensus clustering, we identified 3 subgroups showing unique DNA methylation profiles. Subsequently, we assessed differentially methylated positions (DMPs). Differentially hypermethylated positions (hyper‐DMPs) were significantly more enriched in Group 3 ( n = 82) ( P < 0.001), while differentially hypomethylated positions (hypo‐DMPs) were more prominent in Group 1 ( n = 125). Group 1 was significantly enriched for SF3B1 (46%) mutations ( q <0.01), while Group 2 ( n = 131) was characterized by the enrichment of ASXL1 (38%), RUNX1 (30%), TP53 (26%), STAG2 (15%), and SETBP1 (6.7%) mutations ( q <0.01). In contrast, Group 3 ( n = 64) was significantly enriched for TET2 (67%) and IDH1 / 2 (12% and 15%, respectively) mutations ( q <0.01). Therefore, TET2 and IDH1 / 2 mutations were significantly associated with hyper‐DMPs, which involved 1,891 and 8,330 promotor sites, respectively. Conspicuously, among these hypermethylated promoter sites, >1,616 were commonly hypermethylated, strongly supporting the common impact of TET2 and IDH1/2 mutations on deregulated DNA methylation. Clinically, patients in Group 3 showed significantly shorter overall survival (OS) compared to Group 1 (HR: 1.94, 95%CI: 1.11–3.4, P < 0.05) and OS was even worse in Group 2 patients ( vs. Group 1: HR: 5.18, 95%CI: 3.21–8.36, P < 0.001). Strong correlations between epigenetic and genetic profiles were further interrogated using a Bayesian statistical model. The original 3 clusters were re‐classified into 5 discrete clusters; patients in Group 1 and 3 largely clustered into Cluster A and E, respectively, while Group 2 was further subclassified into clusters B, C, and D. Clusters B and D were characterized by a conspicuous enrichment of DNMT3A (88%) and TP53 (69%) mutations ( q <0.001), while Cluster C was characterized by higher frequency of ASXL1 (71%), RUNX1 (54%), STAG2 (27%), and EZH2 (21%) mutations ( q <0.001). In contrast to such significant associations between epigenetic regulators and unique methylation clusters, splice factor mutations tended to be clustered into multiple clusters, depending on type of co‐occurring mutations. For example, combined SF3B1 and TET2 mutations ( n = 20) were enriched in Cluster A, where highly associated with MDS‐RS, while patients with SF3B1 and RUNX1 mutations ( n = 9) were more grouped in Cluster C, mostly showing MDS‐EB phenotype (89%). Similarly, SRSF2 mutations with RUNX1 and/or ASXL1 mutations ( n = 36) were enriched in Cluster C, largely associated with MDS‐EB phenotype (80%), while those with TET2 or IDH1 / 2 ( n = 39) were mainly grouped into Cluster E, many of which showed MDS‐EB phenotype (74%). These findings highlight differential roles of mutated epigenetic regulators and splicing factors in abnormal DNA methylation. Summary/Conclusion: In conclusion, we elucidated the collaborative impact of DNA methylation profiles and mutation status on heterogeneous pathogenesis and prognosis in MDS. image
RUNX1
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AbstractThe discovery of a family of highly conserved DNA cytosine methylases in honey bees and other insects suggests that, like mammals, invertebrates possess a mechanism for storing epigenetic information that controls heritable states of gene expression. Recent data also show that silencing DNA methylation in young larvae mimics the effects of nutrition on early developmental processes that determine the reproductive fate of honey bee females. We evaluate the impact of these findings on future studies of environmentally-driven phenotypic plasticity in social insects, and discuss how they may help in understanding the nutritional basis of epigenetic reprogramming in humans.
Reprogramming
Epigenesis
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