scholarly journals Aberrant Methylation and Decreased Expression of NRIP1 in IGHV-Unmutated CLL

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1527-1527
Author(s):  
Madelyn Gerber ◽  
Yali Zhu ◽  
Yue-Zhong Wu ◽  
Brian Giacopelli ◽  
Kevin Coombes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
B Cells ◽  
Genomic Dna ◽  
Correlation Coefficients ◽  
Differential Methylation ◽  
Aberrant Methylation ◽  
Transcript Levels ◽  
Methylation Frequency ◽  
Low Expression

Abstract Aberrant DNA methylation patterning occurs in many cancers, including chronic lymphocytic leukemia (CLL). Methylation programming changes as B cells differentiate from immature progenitors to mature B cells. CLL clones originate from a continuum of B cell maturation states, which differ in their "methylome." Emerging evidence suggests that aberrant methylation programming occurs at numerous genes that are differentially expressed in IGHV-defined CLL subtypes. Nuclear receptor interacting protein 1 (NRIP1) reproducibly shows significant gene expression differences in IGHV unmutated (U-CLL) and mutated CLL (M-CLL), with lower transcript levels observed in U-CLL cells. Low expression of NRIP1 is associated with poorer overall survival and time-to-treatment. NRIP1 encodes a cofactor that interacts with various nuclear receptors and other proteins to regulate transcription of genes involved in cellular proliferation, survival, metabolism, inflammation, and other processes. Published data reveal several CpG dinucleotides near the NRIP1 promoter that undergo increasing methylation during the maturation and differentiation of normal peripheral blood B cells (NBC), concordant with a stepwise decrease in transcript levels of NRIP1 over the course of maturation. Interestingly, our analysis of publically available expression data revealed significantly lower NRIP1 expression in U-CLL cells (the less mature CLL subtype) than NBC, while M-CLL cells (the more mature CLL subtype) express levels comparable to NBC. Given these observations, our objective was to interrogate the promoter and regulatory regions at the NRIP1 locus for differences in CpG methylation in genomic DNA isolated from U-CLL, M-CLL, and NBC. We hypothesized that the NRIP1 locus is more highly methylated in U-CLL than in M-CLL and NBC, and that this increased methylation represses NRIP1 gene transcription, contributing to its aberrantly low expression in U-CLL compared to M-CLL and NBC. We bisulfite-converted genomic DNA from negatively-selected CD19+ treatment-naïve CLL samples (n=74 U-CLL, n=37 M-CLL) and NBC from healthy donors (n=5). We PCR-amplified regions in or near the CpG island of NRIP1 and used Agena Bioscience's EpiTyper kit to prepare the samples for analysis on a MassARRAY spectrometer. EpiTyper software was used to detect mass differences that indicate either non-methylated or methylated CpG-containing fragments, and to calculate their relative frequency in each sample. For each CpG locus that was assayed, we fit a beta-regression model to detect differential methylation between M-CLL and U-CLL. We also computed Pearson correlation coefficients comparing methylation levels to gene expression levels. We assessed 47 CpGs mapping to the promoter and nearby regulatory elements of NRIP1 for methylation frequency and correlation with NRIP1 expression. From our comparison of methylation frequency in U-CLL and M-CLL, 3 adjacent CpG loci were significant at false discovery rate (FDR) =1% (CpG 58, p=0.00016; CpG 144, p=0.00062; and CpG 155, p=0.00287). The three most significant correlation coefficients arose from the same three CpG loci (CpG 58, R=0.677, p=2.2e-16; CpG 144, R=0.539, p=7.16e-10; CpG 155, R=0.651, p=5.77e-15). Unexpectedly, all 3 loci were methylated at higher levels in M-CLL and at lower levels in U-CLL (on average), and expression was positively correlated with methylation levels. These CpGs map near a documented binding site for the repressive transcription factor RUNX3, prompting us to hypothesize that differential methylation in U-CLL versus M-CLL may affect the binding affinity of RUNX3 and contribute to the robust NRIP1 expression differences in these CLL subtypes. Future work will test this hypothesis using gel-shift and luciferase reporter assays followed by chromatin immunoprecipitation experiments. Few studies have focused on aberrant methylation patterning in CLL and the consequences of deregulated gene expression. We are the first to look at NRIP1 for differences in DNA methylation across IGHV subtypes. Future studies aimed at understanding how methylation at this locus affects NRIP1 transcription, as well as how levels of NRIP1 affect cell survival pathways, will enhance our understanding of the role of this gene in CLL, and the contributions of deregulated methylation to disease pathophysiology. Disclosures No relevant conflicts of interest to declare.

Epigenetic Profiling of Primary CLL Reveals Novel DNA Methylation-Based Clusters and Novel Mechanisms of Leukemogenesis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3877-3877
Author(s):  
Fong Fong ◽  
Haim Y Bar ◽  
Kerby Shedden ◽  
Kamlai saiya-Cork ◽  
Peter Ouillette ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
B Cells ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Methylation Status ◽  
Snp Array ◽  
Aberrant Methylation ◽  
Unequal Variance ◽  
Genomic Deletions

Abstract Abstract 3877 Introduction: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the Western world with nearly 15,000 new cases diagnosed every year in the USA. The characterization of CLL has resulted in the identification of important disease biomarkers: these include the recurrent genomic deletions del17p and del11q, genomic complexity, TP53 mutations, the expression level of ZAP70 and the mutational status of IgVH. While genomic and transcriptional profiling of CLL identified clinically and biologically relevant markers, there is still significant uncertainty about the pathobiology and the origin of CLL. It is increasingly clear that epigenetic deregulation plays an important role in the biology of all lymphomas/leukemias including CLL. Methods: We hypothesized that DNA methylation profiling would allow us to identify new, biologically significant CLL subtypes and yield greater insight into the biology of this disease. We therefore examined the DNA methylation of over 240 patients with CLL using the HELP assay and hybridization to high density custom microarray that reports on the methylation status of more than 250,000 CpGs corresponding to 20,401 genes. Gene expression profiling and SNP array-based copy number assessments and targeted gene resequencing were available on most of these cases. We performed unsupervised analysis on the most variable probesets (standard deviation > 1.3) using K-means consensus clustering. Results: The experimental approach reproducibly identified three robust CLL subtypes based on epigenetic profiles. To identify the genes that define these three subtypes we next performed unequal variance t-test of the CLL subtypes comparing them to Peripheral Blood CD19+ B cells as a normal control, and identified that clusters are defined by differential methylation of 3719, 6145 and 3349 genes (selected probes displayed changes in methylation of at least 30% and FDR corrected p-value < 0.05), The three clusters featured respectively i) aberrant methylation of MYC and WNT target genes, ii) aberrant methylation of NOTCH1 targets and iii) aberrant methylation of bcl6 and inflammatory cytokines. There was inverse correlation between gene expression and cytosine methylation, suggesting that DNA methylation had an impact on the transcriptional programming of these CLL cases. Strikingly the CLL MYC/WNT cluster displayed poorer prognosis as opposed to the CLL BCL6 cluster (HR=0.14 95% CI: 0.07–0.30). The CLL NOTCH1 cluster had an intermediate prognosis. It was also notable that all CLL patients exhibited deregulation of the B-cell receptor pathway as compared to normal CD19+ B-cells, consistent with the notion that this pathway plays a critical role in CLL pathogenesis. Finally, we divided the cohort into training and testing cohorts and used a machine learning BDVAL algorithm to identify DNA methylation outcome classifiers. This procedure identified a 40-probeset classifier that accurately predicted outcome (Area Under the ROC Curve of 0.77; performance was assessed with 10 fold cross-validation in a training set with 76 patients; validation on an independent set of 105 samples). Conclusion: This large epigenetic profiling study in CLL identifies aberrant epigenetic regulation as a core part of the pathobiology of CLL and identifies novel CLL clusters with distinct effects on survival. MYC-WNT pathway inhibitors are warranted for use in clinical trials for patients belonging to this aggressive epigenetically defined subtype. Disclosures: No relevant conflicts of interest to declare.

Low Expression of SCN4B Correlated with DNA Hypermethylation and Poor Prognosis in Non-small Cell Lung Cancer

2021 ◽  
Author(s):  
Meixiang Yu ◽  
Zi Wang ◽  
Qianzhou Lv ◽  
Wanhua Yang
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Poor Prognosis ◽  
Small Cell ◽  
Clinical Grade ◽  
Small Cell Lung ◽  
Immunohistochemistry Staining ◽  
Kaplan Meier ◽  
Nsclc Patients ◽  
Low Expression

Abstract Background:Voltage-gated sodium channels β subunits 4 (SCN4B), a tumor suppressor, was previously reported to be associated with DNA methylation and poor prognosis in multiple cancers except lung cancer. This study aimed to explore whether the low expression of SCN4B was correlated with DNA methylation and clinical prognosis in non-small cell lung cancer (NSCLC) . Methods:The gene expression profiles (GDS3837and GSE50081) were extracted from Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) analysis was performed to explore the expression of SCN4B in NSCLC tissue compared with normal tissue, with the cut-off value p < 0.05 and the absolute value of the log2 fold change ≥ 1.5. Immunohistochemistry staining was used to validated its expression using The Human Protein Atlas database. And MPRESS was used to analysis the relations of SCN4B expression between DNA methylation. Then, the Fisher exact and Wilcoxon rank-sum tests were used to calculate the associations of SCN4B expression with NSCLC clinicopathological features such as clinical grade and tumor node metastasis (TNM) stage, while Kaplan–Meier survival analysis and cox regression analysis were performed to estimate the prognostic value of SCN4B expression in NSCLC. Results: Our DEGS analysis results showed a significantly decreased expression of SCN4B (p=6.5e-22) in NSCLC, which were validated by immunohistochemistry staining. Besides, this decreasing trend continued as the clinical grade and T stage advanced (p<0.05). There was a negative correlation between the SCN4B expression and DNA promoter methylation (p<0.01). Kaplan–Meier survival analysis indicated that NSCLC patients with low expression of SCN4B had a worse prognosis than those with high expression (p < 0.004). Meanwhile, univariate and multivariate analysis indicated SCN4B expression was an independent unfavorable prognostic factor for OS in NSCLC (Hazard Ratio= 0.236, p = 0.009; Hazard Ratio=0.219, p = 0.003, respectively).Conclusions: SCN4B expression was significantly downregulated in NSCLC, which might be attributed to DNA promoter hypermethylation. The low expression of SCN4B indicated a potential unfavorable prognostic factor for NSCLC patients.

Abstract 15: Glucose-Mediated Remodeling of Cardiac DNA Methylation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Mark E Pepin ◽  
David K Crossman ◽  
Joseph P Barchue ◽  
Salpy V Pamboukian ◽  
Steven M Pogwizd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Dna Methylation ◽  
Diabetic Cardiomyopathy ◽  
Left Ventricular ◽  
Epigenetic Mark ◽  
Gene Transcript ◽  
Transcript Levels ◽  
Glycemic Memory

To identify the role of glucose in the development of diabetic cardiomyopathy, we had directly assessed glucose delivery to the intact heart on alterations of DNA methylation and gene expression using both an inducible heart-specific transgene (glucose transporter 4; mG4H) and streptozotocin-induced diabetes (STZ) mouse models. We aimed to determine whether long-lasting diabetic complications arise from prior transient exposure to hyperglycemia via a process termed “glycemic memory.” We had identified DNA methylation changes associated with significant gene expression regulation. Comparing our results from STZ, mG4H, and the modifications which persist following transgene silencing, we now provide evidence for cardiac DNA methylation as a persistent epigenetic mark contributing to glycemic memory. To begin to determine which changes contribute to human heart failure, we measured both RNA transcript levels and whole-genome DNA methylation in heart failure biopsy samples (n = 12) from male patients collected at left ventricular assist device placement using RNA-sequencing and Methylation450 assay, respectively. We hypothesized that epigenetic changes such as DNA methylation distinguish between heart failure etiologies. Our findings demonstrated that type 2 diabetic heart failure patients (n = 6) had an overall signature of hypomethylation, whereas patients listed as ischemic (n = 5) had a distinct hypermethylation signature for regulated transcripts. The focus of this initial analysis was on promoter-associated CpG islands with inverse changes in gene transcript levels, from which diabetes (14 genes; e.g. IGFBP4) and ischemic (12 genes; e.g. PFKFB3) specific targets emerged with significant regulation of both measures. By combining our mouse and human molecular analyses, we provide evidence that diabetes mellitus governs direct regulation of cellular function by DNA methylation and the corresponding gene expression in diabetic mouse and human hearts. Importantly, many of the changes seen in either mouse type 1 diabetes or human type 2 diabetes were similar supporting a consistent mechanism of regulation. These studies are some of the first steps at defining mechanisms of epigenetic regulation in diabetic cardiomyopathy.

scholarly journals Cadmium-associated differential methylation throughout the placental genome: epigenome-wide association study of two US birth cohorts

2017 ◽  
Author(s):  
Todd M. Everson ◽  
Tracy Punshon ◽  
Brian P. Jackson ◽  
Ke Hao ◽  
Luca Lambertini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Fetal Development ◽  
Meta Analysis ◽  
Reproductive Toxicity ◽  
Differential Methylation ◽  
Cellular Growth ◽  
Birth Cohorts ◽  
Inflammatory Signaling ◽  
P Values

AbstractBackgroundCadmium (Cd) is a ubiquitous toxicant that during pregnancy can impair fetal development. Cd sequesters in the placenta where it can impair placental function, impacting fetal development. We aimed to investigate Cd-associated variations in placental DNA methylation (DNAM), associations with gene expression, and identify novel pathways involved in Cd-associated reproductive toxicity.MethodsUsing placental DNAM and Cd concentrations in the New Hampshire Birth Cohort Study (NHBCS, n=343) and the Rhode Island Child Health Study (RICHS, n=141), we performed an EWAS between Cd and DNAM, adjusting for tissue heterogeneity using a reference-free method. Cohort-specific results were aggregated via inverse variance weighted fixed effects meta-analysis, and variably methylated CpGs were associated with gene expression. We then performed functional enrichment analysis and tests for associations between gene expression and birth metrics.ResultsWe identified 17 Cd-associated differentially methylated CpG sites with meta-analysis p-values < 1e-05, two of which were within a 5% false discovery rate (FDR). Methylation levels at 9 of the 17 loci were associated with increased expression of 6 genes (5% FDR): TNFAIP2, EXOC3L4, GAS7, SREBF1, ACOT7, and RORA. Higher placental expression of TNFAIP2 and ACOT7, and lower expression of RORA, were associated with lower birth weight z-scores (p-values < 0.05).ConclusionCd associated differential DNAM and corresponding DNAM-expression associations at these loci are involved in inflammatory signaling and cell growth. The expression levels of genes involved in inflammatory signaling (TNFAIP2, ACOT7, and RORA), were also associated with birth metrics, suggesting a role for inflammatory processes in Cd-associated reproductive toxicity.SignificanceCadmium is a toxic environmental pollutant that can impair fetal development. The mechanisms underlying this toxicity are unclear, though disrupted placental functions could play an important role. In this study we examined associations between cadmium concentrations and DNA methylation throughout the placental genome, across two US birth cohorts. We observed cadmium-associated differential methylation, and corresponding methylation-expression associations at genes involved in cellular growth processes and/or immune and inflammatory signaling. This study provides supporting evidence that disrupted placental epigenetic regulation of cellular growth and immune/inflammatory signaling could play a role in cadmium associated reproductive toxicity in human pregnancies.

scholarly journals DNA methylation profile of psoriatic skins from different body locations

Epigenomics ◽  
2019 ◽  
Vol 11 (14) ◽  
pp. 1613-1625 ◽  
Author(s):  
Mingshun Wu ◽  
Xueying Li ◽  
Chaowen Zhang ◽  
Chuanliang Zhang ◽  
Danfeng Qian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Differential Methylation ◽  
Methylation Profile ◽  
Anatomical Location ◽  
Pathological Features ◽  
Target Region ◽  
Dna Methylation Profile ◽  
Control Skin ◽  
Skin Samples

Aim: To understand whether the anatomical location of origin plays a role in shaping the DNA methylation (DNAm) landscape of psoriatic skins. Patients & methods: A number of 108 psoriatic and 57 control skin samples were grouped based on their anatomical locations. Two group t-tests were used to identify those differentially methylated sites and regions. Target region methylation loci were validated by bisulfate conversion sequencing. The correlations of DNAm with pathological features, DNAm and gene expression were also interrogated. Results: Our analysis revealed 315 location-specific differentially methylated sites for back, 291 for the extremities and 801 for abdomen. Moreover, we observed that the extremity-specific loci cg21942490 located on HOXA9 is associated with hyperkeratosis. We further observed that HOXA5 and KIAA1949 are differential methylation regions. Conclusion: Our study shown evidence of anatomical location-dependent DNAm pattern in psoriasis skins, and thus provided new insights into the pathogenesis of this disease.

scholarly journals X chromosome-wide analyses of genomic DNA methylation states and gene expression in male and female neutrophils

2010 ◽  
Vol 107 (8) ◽  
pp. 3704-3709 ◽  
Author(s):  
Yukio Yasukochi ◽  
Osamu Maruyama ◽  
Milind C. Mahajan ◽  
Carolyn Padden ◽  
Ghia M. Euskirchen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
X Chromosome ◽  
Genomic Dna ◽  
Male And Female

DNA Methyltransferase 1 Contributes to Epigenetic Signatures and Biological Phenotype during Normal B-Cell Differentiation and Lymphomagenesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 685-685 ◽  
Author(s):  
Rita Shaknovich ◽  
Leandro Cerchietti ◽  
Maria E. Figueroa ◽  
Ari Melnick
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Dna Methyltransferase ◽  
Critical Role ◽  
Epigenetic Programming ◽  
Differential Digestion ◽  
Epigenetic Signatures

Abstract Normal hematopoiesis requires incremental changes in gene expression in order to establish cellular phenotypes with specialized functions. We are particularly interested in the transcriptional and epigenetic programming of germinal center (GC) B-cells, which acquire unusual biological features normally associated with cancer. Specifically, GC B-cells (i.e. centroblasts - CB) undergo rapid DNA replication while at the same time undergoing genetic recombination, and give rise to a majority of B-cell lymphomas. We hypothesized that epigenetic programming would play a critical role in the CB stage of development, and that gene-specific and genome-wide DNA methyltransferase activity is critical for these cells. We first examined the CpG methylation levels of 24,000 gene promoters in five sets of primary human B-cells just prior to (i.e. naïve B-cells - NBC) and upon entering the GC reaction (i.e. CBs). This was achieved using the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay, which relies on differential digestion of genomic DNA by the isoschizomer enzymes HpaII and Msp. HELP is a robust and reproducible method that provides accurate and quantitative measurement of DNA methylation levels throughout the genome. Remarkably, we found that the DNA methylation profile of B-cells undergoes a significant shift as readily appreciated by hierarchical clustering. The epigenetic signatures of NBC and CB are differentiation-stage dependent and do not vary significantly between individuals. The coefficient of correlation between individuals was 0.98, as compared to the NBC vs. CB fractions 0.92–0.95. Supervised analysis demonstrated that 266 genes (P<0.001) were differentially methylated upon entry of NB-cells into the GC reaction. We further correlated the methylation status of these genes with their gene expression level. The most heavily affected pathways by differential methylation and concordant expression in naïve B-cells were the Jak/STAT and MAP3K signaling pathways, while in CBs the p38 MAPK pathway and Ikaros family of genes were most affected. Given the epigenetic reprogramming observed in CBs vs. NBCs, along with the need for maintenance of methylation during rapid replication, we predicted that DNA methyltransferase (DNMT) enzymes play a critical role in centroblasts. By performing QPCR and Western blots on isolated fractions of human tonsilar lymphocytes and anatomical localization by immunohistochemistry, we found that DNMTs have a complex temporal and combinatorial expression pattern whereby DNMT1 was the main methyltransferase detectable in centroblasts. Additionally we studied 10 DLBCL cell lines and a panel of primary DLBCL (n=176 for mRNA and 70 for protein) for DNMTs expression. Spearman Rank correlation analysis revealed that DNMT1 was preferentially highly expressed in GCB vs. ABC primary DLBCLs, as well as in BCR vs. OxPhos DLBCLs. Taken together, our data suggest that i) dynamic changes in epigenetic programming contribute to formation of GCs, ii) that DNMT1 may play both a de novo and maintenance methylation role in GC cells, iii) that DNMT1 is markedly upregulated in normal centroblasts and in DLBCLs with the BCR or GCB gene expression profiles and iv) specific therapeutic targeting of DNMT1 rather than non-specific global inhibition of DNA methylation could be a useful anti-lymphoma strategy for germinal center-derived DLBCLs.

Genome-Wide DNA Methylation Analysis Shows Enrichment of Differential Methylation in “Open Seas” and Enhancers and Reveals Hypomethylation in DNMT3A Mutated Cytogenetically Normal AML (CN-AML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 653-653 ◽  
Author(s):  
Ying Qu ◽  
Andreas Lennartsson ◽  
Verena I. Gaidzik ◽  
Stefan Deneberg ◽  
Sofia Bengtzén ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cpg Island ◽  
Cpg Islands ◽  
Differential Methylation ◽  
Methylation Analysis ◽  
Cpg Sites ◽  
Genome Wide ◽  
Genomic Regions ◽  
Methylation Patterns

Abstract Abstract 653 DNA methylation is involved in multiple biologic processes including normal cell differentiation and tumorigenesis. In AML, methylation patterns have been shown to differ significantly from normal hematopoietic cells. Most studies of DNA methylation in AML have previously focused on CpG islands within the promoter of genes, representing only a very small proportion of the DNA methylome. In this study, we performed genome-wide methylation analysis of 62 AML patients with CN-AML and CD34 positive cells from healthy controls by Illumina HumanMethylation450K Array covering 450.000 CpG sites in CpG islands as well as genomic regions far from CpG islands. Differentially methylated CpG sites (DMS) between CN-AML and normal hematopoietic cells were calculated and the most significant enrichment of DMS was found in regions more than 4kb from CpG Islands, in the so called open sea where hypomethylation was the dominant form of aberrant methylation. In contrast, CpG islands were not enriched for DMS and DMS in CpG islands were dominated by hypermethylation. DMS successively further away from CpG islands in CpG island shores (up to 2kb from CpG Island) and shelves (from 2kb to 4kb from Island) showed increasing degree of hypomethylation in AML cells. Among regions defined by their relation to gene structures, CpG dinucleotide located in theoretic enhancers were found to be the most enriched for DMS (Chi χ2<0.0001) with the majority of DMS showing decreased methylation compared to CD34 normal controls. To address the relation to gene expression, GEP (gene expression profiling) by microarray was carried out on 32 of the CN-AML patients. Totally, 339723 CpG sites covering 18879 genes were addressed on both platforms. CpG methylation in CpG islands showed the most pronounced anti-correlation (spearman ρ =-0.4145) with gene expression level, followed by CpG island shores (mean spearman rho for both sides' shore ρ=-0.2350). As transcription factors (TFs) have shown to be crucial for AML development, we especially studied differential methylation of an unbiased selection of 1638 TFs. The most enriched differential methylation between CN-AML and normal CD34 positive cells were found in TFs known to be involved in hematopoiesis and with Wilms tumor protein-1 (WT1), activator protein 1 (AP-1) and runt-related transcription factor 1 (RUNX1) being the most differentially methylated TFs. The differential methylation in WT 1 and RUNX1 was located in intragenic regions which were confirmed by pyro-sequencing. AML cases were characterized with respect to mutations in FLT3, NPM1, IDH1, IDH2 and DNMT3A. Correlation analysis between genome wide methylation patterns and mutational status showed statistically significant hypomethylation of CpG Island (p<0.0001) and to a lesser extent CpG island shores (p<0.001) and the presence of DNMT3A mutations. This links DNMT3A mutations for the first time to a hypomethylated phenotype. Further analyses correlating methylation patterns to other clinical data such as clinical outcome are ongoing. In conclusion, our study revealed that non-CpG island regions and in particular enhancers are the most aberrantly methylated genomic regions in AML and that WT 1 and RUNX1 are the most differentially methylated TFs. Furthermore, our data suggests a hypomethylated phenotype in DNMT3A mutated AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Invertebrate DNA Methylation and Gene Regulation

2021 ◽  
Author(s):  
Groves Dixon ◽  
Mikhail Matz
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Gene Regulation ◽  
Environmental Change ◽  
Linear Relationship ◽  
Differential Expression ◽  
Differential Methylation ◽  
Simple Relationship ◽  
Simple Linear Relationship

Abstract BackgroundAs human activity alters the planet, there is a pressing need to understand how organisms adapt to environmental change. Of growing interest in this area is the role of epigenetic modifications, such as DNA methylation, in tailoring gene expression to fit novel conditions. Here, we reanalyzed nine invertebrate (Anthozoa and Hexapoda) datasets to validate a key prediction of this hypothesis: changes in DNA methylation in response to some condition correlate with changes in gene expression. ResultsWhile we detected both differential methylation and differential expression, there was no simple relationship between these differences. ConclusionIf changes in DNA methylation regulate invertebrate transcription, the mechanism does not follow a simple linear relationship.

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