Deficiency in Vitamin B12 and Ferritin Is Associated With Epigenetic Alterations in Cancer Patients  

2021 ◽  
Author(s):  
Khaled A. Elawdan ◽  
Sabah Farouk ◽  
Salah Araf ◽  
Hany Khalil
Keyword(s):  
Dna Methylation ◽  
Vitamin B12 ◽  
Cancer Patients ◽  
Promoter Region ◽  
Dna Methyltransferases ◽  
Epigenetic Alterations ◽  
Promoter Regions ◽  
Methylation Sensitive Restriction Enzyme ◽  
Low Levels ◽  
Dna Methylation Analysis

Abstract Background: Cancer is the second-leading cause of death worldwide, caused by several mutations in DNA within the cells including epigenetic alteration. The epigenetic changes are external modifications to the DNA that switch “on” or “off” gene expression. The present study was conducted to investigate the epigenetic modifications and its correlation with the levels of vitamin B12 and ferritin in cancer patients with hepatocellular carcinoma (HCC), breast cancer (BC), lung cancer (LC), or colon cancer (CC). Methods and Results: A total of 200 blood samples were obtained from cancer patients and healthy individuals. The relative expression of DNA methyltransferases (DNMTs), Ten-Eleven translocation (TET), and methionine synthase (MS) was evaluated in patients with the normal level of vitamin B12/ferritin and patients with the deficient levels of them. DNA methylation within the promoter regions was investigated of each indicated genes using the methylation-sensitive restriction enzyme HpaII and bisulfite PCR. Interestingly, the expression of DNMT1, DNMT3a, and DNMT3b was increased in patients with low levels of vitamin B12 and ferritin, while the expression of MS, TET1, and TET3 was significantly decreased. DNA methylation analysis in patients with deficient levels of vitamin B12/ferritin showed a methylated-cytosine within the location 318/CG and 385/CG in the promoter region of TET1 and TET3, respectively. Moreover, the bisulfite PCR assay further confirmed the methylation changes in the promoter region of TET1 and TET3 at the indicated locations. Conclusion: These data indicate that the deficiency in vitamin B12 and ferritin in cancer patients plays a key role in the epigenetic exchanges during cancer development.

Deficiency in vitamin B12 and ferritin is associated with epigenetic alterations in cancer patients

2021 ◽  
Author(s):  
Khaled A. Elawdan ◽  
Sabah Farouk ◽  
Salah Araf ◽  
Hany Khalil
Keyword(s):  
Dna Methylation ◽  
Vitamin B12 ◽  
Cancer Patients ◽  
Promoter Region ◽  
Dna Methyltransferases ◽  
Epigenetic Alterations ◽  
Promoter Regions ◽  
Methylation Sensitive Restriction Enzyme ◽  
Low Levels ◽  
Dna Methylation Analysis

Abstract Background: Cancer is the second-leading cause of death worldwide, caused by several mutations in DNA within the cells including epigenetic alteration. The epigenetic changes are external modifications to the DNA that switch “on” or “off” gene expression. The present study was conducted to investigate the epigenetic modifications and its correlation with the levels of vitamin B12 and ferritin in cancer patients with hepatocellular carcinoma (HCC), breast cancer (BC), lung cancer (LC), or colon cancer (CC). Methods and Results: A total of 200 blood samples were obtained from cancer patients and healthy individuals. The relative expression of DNA methyltransferases (DNMTs), Ten-Eleven translocation (TET), and methionine synthase (MS) was evaluated in patients with the normal level of vitamin B12/ferritin and patients with the deficient levels of them. DNA methylation within the promoter regions was investigated of each indicated genes using the methylation-sensitive restriction enzyme HpaII and bisulfite PCR. Interestingly, the expression of DNMT1, DNMT3a, and DNMT3b was increased in patients with low levels of vitamin B12 and ferritin, while the expression of MS, TET1, and TET3 was significantly decreased. DNA methylation analysis in patients with deficient levels of vitamin B12/ferritin showed a methylated-cytosine within the location 318/CG and 385/CG in the promoter region of TET1 and TET3, respectively. Moreover, the bisulfite PCR assay further confirmed the methylation changes in the promoter region of TET1 and TET3 at the indicated locations. Conclusion: These data indicate that the deficiency in vitamin B12 and ferritin in cancer patients plays a key role in the epigenetic exchanges during cancer development.

EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

2008 ◽  
Vol 31 (4) ◽  
pp. 11
Author(s):  
Manda Ghahremani ◽  
Courtney W Hannah ◽  
Maria Peneherrera ◽  
Karla L Bretherick ◽  
Margo R Fluker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Premature Ovarian Failure ◽  
Promoter Region ◽  
Gene Promoter ◽  
Ovarian Failure ◽  
P Value ◽  
Epigenetic Alterations ◽  
Methylation Array ◽  
Cpg Sites ◽  
Deficient Mice

Background/Purpose: Premature ovarian failure (POF) affects 1% of women with a largely idiopathic and poorly understood etiology. The objective of this study was to identify specific epigenetic alterations by measuring DNA methylation of gene regulatory regions in women with POF vs. controls. Methods: Blood samples were collected from idiopathic POFpatients (Amenorrhea for at least 3 months and 2 serum FSH levels of > 40mIU/ml obtained > 1 month apart prior to age 40) and control women (CW) (healthy pregnancy after age 37 with out a pregnancy loss). Genomic DNA was extracted from EDTA anticoagulated blood and bisulfite converted for analysis using the Illumina Golden Gate Methylation Panel which measures DNA methylation at 1506 CpG sites in the promoter regions of 807 genes in 10 POF and 12 CW. Candidate genes with altered epigenetic marks between POF and CW at a nominal P-value < 0.05 were identified using a t-testcomparison within the Illumina bead studio software. Genes of interest were further analyzed for quantitative methylation at specific CpG sites using pyrosequencing in 30 POF and 30 CW. Results: Comparison of DNA methylation profiles of our initial POF and CW groups identified several genes with statistically significanthyper- or hypo- methylation in the POF group (P < 0.05), including the Androgen Receptor (AR)promoter region, which was significantly hypermethylated. To further validate these results, DNA methylation of the AR gene promoter was quantified bypryosequencing in a larger group of POF and CW. Pyrosequencing further confirmed a significantly higher DNA methylation of the AR promoter region inPOF vs. CW (P=0.007). Conclusions: This is a novel study identifying epigenetic alterations in POF. The hypermethylation of the AR gene in POF patients may cause decreased level of the AR in these women. This is especially interesting given a recent report of induced POF in AR deficient mice^1. Specific epigenetic markers, as identified by DNA methylation array profiling in blood, may serve as useful biomarkers for POF and other fertility disorders. However, it will need to be determined if these methylation changes are present prior to diagnosis, or are a consequence of menopause itself. Reference: 1.Hiroko S. et al. Premature ovarian failure in androgenreceptor deficient mice. PNAS;103:224-9

scholarly journals Neuroblastoma and the epigenome

2021 ◽  
Author(s):  
Irfete S. Fetahu ◽  
Sabine Taschner-Mandl
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Disease Diagnosis ◽  
Dna Methyltransferases ◽  
Epigenetic Alterations ◽  
Aberrant Expression ◽  
Tet Proteins ◽  
Relative Paucity ◽  
Underlying Causes ◽  
Aberrant Dna Methylation

AbstractNeuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system and one of the most common solid tumors in infancy. Amplification of MYCN, copy number alterations, numerical and segmental chromosomal aberrations, mutations, and rearrangements on a handful of genes, such as ALK, ATRX, TP53, RAS/MAPK pathway genes, and TERT, are attributed as underlying causes that give rise to NB. However, the heterogeneous nature of the disease—along with the relative paucity of recurrent somatic mutations—reinforces the need to understand the interplay of genetic factors and epigenetic alterations in the context of NB. Epigenetic mechanisms tightly control gene expression, embryogenesis, imprinting, chromosomal stability, and tumorigenesis, thereby playing a pivotal role in physio- and pathological settings. The main epigenetic alterations include aberrant DNA methylation, disrupted patterns of posttranslational histone modifications, alterations in chromatin composition and/or architecture, and aberrant expression of non-coding RNAs. DNA methylation and demethylation are mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, respectively, while histone modifications are coordinated by histone acetyltransferases and deacetylases (HATs, HDACs), and histone methyltransferases and demethylases (HMTs, HDMs). This article focuses predominately on the crosstalk between the epigenome and NB, and the implications it has on disease diagnosis and treatment.

scholarly journals Multiplexed DNA Methylation Analysis in Colorectal Cancer Using Liquid Biopsy and Its Diagnostic and Predictive Value

2021 ◽  
Vol 43 (3) ◽  
pp. 1419-1435
Author(s):  
Walter Pulverer ◽  
Kristi Kruusmaa ◽  
Silvia Schönthaler ◽  
Jasmin Huber ◽  
Marko Bitenc ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Therapy Monitoring ◽  
Methylation Status ◽  
Methylation Analysis ◽  
Microarray Experiments ◽  
Specific Pcr ◽  
Colonic Adenomas ◽  
Methylation Sensitive Restriction Enzyme ◽  
Dna Methylation Analysis

Early diagnosis of colorectal cancer (CRC) is of high importance as prognosis depends on tumour stage at the time of diagnosis. Detection of tumour-specific DNA methylation marks in cfDNA has several advantages over other approaches and has great potential for solving diagnostic needs. We report here the identification of DNA methylation biomarkers for CRC and give insights in our methylation-sensitive restriction enzyme coupled qPCR (MSRE-qPCR) system. Targeted microarrays were used to investigate the DNA methylation status of 360 cancer-associated genes. Validation was done by qPCR-based approaches. A focus was on investigating marker performance in cfDNA from 88 patients (44 CRC, 44 controls). Finally, the workflow was scaled-up to perform 180plex analysis on 110 cfDNA samples, to identify a DNA methylation signature for advanced colonic adenomas (AA). A DNA methylation signature (n = 44) was deduced from microarray experiments and confirmed by quantitative methylation-specific PCR (qMSP) and by MSRE-qPCR, providing for six genes’ single areas under the curve (AUC) values of >0.85 (WT1, PENK, SPARC, GDNF, TMEFF2, DCC). A subset of the signatures can be used for patient stratification and therapy monitoring for progressed CRC with liver metastasis using cfDNA. Furthermore, we identified a 35-plex classifier for the identification of AAs with an AUC of 0.80.

scholarly journals Mining the Selective Remodeling of DNA Methylation in Promoter Regions to Identify Robust Gene-Level Associations With Phenotype

2021 ◽  
Vol 8 ◽  
Author(s):  
Yuan Quan ◽  
Fengji Liang ◽  
Si-Min Deng ◽  
Yuexing Zhu ◽  
Ying Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Region ◽  
Biological Significance ◽  
Biological Efficiency ◽  
Body Region ◽  
Promoter Regions ◽  
Exposure Factor ◽  
Epigenetic Events ◽  
Gene Level ◽  
Disease Related Gene

Epigenetics is an essential biological frontier linking genetics to the environment, where DNA methylation is one of the most studied epigenetic events. In recent years, through the epigenome-wide association study (EWAS), researchers have identified thousands of phenotype-related methylation sites. However, the overlaps of identified phenotype-related DNA methylation sites between various studies are often quite small, and it might be due to the fact that methylation remodeling has a certain degree of randomness within the genome. Thus, the identification of robust gene-phenotype associations is crucial to interpreting pathogenesis. How to integrate the methylation values of different sites on the same gene and to mine the DNA methylation at the gene level remains a challenge. A recent study found that the DNA methylation difference of the gene body and promoter region has a strong correlation with gene expression. In this study, we proposed a Statistical difference of DNA Methylation between Promoter and Other Body Region (SIMPO) algorithm to extract DNA methylation values at the gene level. First, by choosing to smoke as an environmental exposure factor, our method led to significant improvements in gene overlaps (from 5 to 17%) between different datasets. In addition, the biological significance of phenotype-related genes identified by SIMPO algorithm is comparable to that of the traditional probe-based methods. Then, we selected two disease contents (e.g., insulin resistance and Parkinson’s disease) to show that the biological efficiency of disease-related gene identification increased from 15.43 to 44.44% (p-value = 1.20e–28). In summary, our results declare that mining the selective remodeling of DNA methylation in promoter regions can identify robust gene-level associations with phenotype, and the characteristic remodeling of a given gene’s promoter region can reflect the essence of disease.

Evaluation of DNA methylation in promoter regions of hTERT, TWIST1, VIM and NID2 genes in Moroccan bladder cancer patients.

2021 ◽  
Author(s):  
Meryem El Azzouzi ◽  
Hajar El Ahanidi ◽  
Chaimae Hafidi Alaoui ◽  
Imane Chaoui ◽  
Laila Benbacer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bladder Cancer ◽  
Cancer Patients ◽  
Promoter Regions

Genome-Wide DNA Methylation Landscape Defines IGHV Mutated and Unmutated B Cell Chronic Lymphocytic Leukemias

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 526-526
Author(s):  
Junfeng Luo ◽  
Justin Choi ◽  
Lirong Pei ◽  
Farrukh Awan ◽  
Eun-Joon Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
B Cells ◽  
B Cell ◽  
Dna Hypomethylation ◽  
Excellent Correlation ◽  
Methylation Analysis ◽  
Promoter Regions ◽  
Genome Wide ◽  
Dna Methylation Analysis

Abstract Abstract 526 Chronic lymphocytic leukemia (CLL) is a biologically and clinically heterogeneous disease. The somatic hypermutation status of the immunoglobulin heavy chain variable (IGHV) genes has been identified as one of the most robust prognostic markers in CLL. Patients with unmutated IGHV status (U-CLL) typically experience an inferior outcome compared to those whose clones express mutated IGHV genes (M-CLL). We conducted a genome-wide DNA methylation analysis in CD19+ B-cells from a group of 43 CLL patients using reduced representation bisulfite sequencing (RRBS). Using base-pair resolution methylation sequencing, 2323 differentially methylated regions between CLL and normal B cells (CLL-specific DMRs) and 569 between M-CLL and U-CLL samples (IGHV-specific DMRs) were identified in the CLL genomes. The IGHV-specific DMRs are mostly unique when compared to the CLL-specific DMRs. Less than 10% of the IGHV-specific DMRs are located in promoter regions; however, more than half of these overlap with known DNase I hypersensitive sites, enhancer regions marked by histone modification (H3K4Me1 and H3K27Ac), and transcription factor binding sites in the ENCODE datasets, which indicates that these DMRs contain regulatory sequences. Distinctive DNA methylation patterns were observed in M-CLL and U-CLL samples. Overall, U-CLL was found to contain 50% more hypermethylated regions than M-CLL samples. The hypermethylated loci observed in the U-CLL samples also appear to be hypermethylated in normal naïve B cells as compared memory B cells, suggesting that M-CLL and U-CLL differ in differentiation status corresponding to normal B cell differentiation stages. RNA-seq analysis performed using matched samples (n=34), in which both DNA methylation and gene expression data were available, demonstrated excellent correlation between DNA methylation and gene expression. Several genes whose expression status was previously shown to be associated with CLL prognosis such as ZAP70, CRY1, LDOC1, SEPT10, LAG3, and LPL were differentially methylated in the promoter regions between M-CLL and U-CLL samples indicating that DNA methylation plays an important role in defining the gene expression patterns of these prognostic genes. We further validated 9 genes with IGHV-specific DMRs in the promoter regions using bisulfite pyrosequencing, and the results demonstrated excellent correlation between differential methylation and IGHV mutation status. These novel differentially methylated genes could be developed into biomarkers for CLL prognosis. In addition, DNA hypomethylation was observed in a significant number of genes involved in lymphocyte activation such as PDCD1, NFATc1, and CD5. DNA hypomethylation was observed in the proximal promoter and far up-stream enhancer regions of CD5, an important cell surface marker that uniquely identifies CLL. Overall, the DNA methylation landscape in CLL patients indicates that CLL B cells possess an active B-cell phenotype; at the same time, U-CLL and M-CLL are faithfully committed to their lineage resembling either naïve or memory B cells. In summary, this comprehensive DNA methylation analysis has identified a large number of novel epigenetic changes in CLL patients. The results from this study will further advance our understanding of the epigenetic contribution to molecular subtypes in CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals DNA methylation subpatterns at distinct regulatory regions in human early embryos

Open Biology ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. 180131 ◽  
Author(s):  
Rongsong Luo ◽  
Chunling Bai ◽  
Lei Yang ◽  
Zhong Zheng ◽  
Guanghua Su ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Correlation Analysis ◽  
Promoter Region ◽  
Promoter Regions ◽  
Regulate Gene Expression ◽  
Early Embryos ◽  
Candidate Promoter ◽  
Single Base Resolution ◽  
Genomic Regions

DNA methylation has been investigated for many years, but recent technologies have allowed for single-cell- and single-base-resolution DNA methylation datasets and more accurate assessment of DNA methylation dynamics at the key genomic regions that regulate gene expression in human early embryonic development. In this study, the region from upstream 20 kb to downstream 20 kb of RefSeq gene was selected and divided into 12 distinct regions (up20, up10, up5, up2, 5'UTR, exon, intron, 3'UTR, down2, down5, down10 and down20). The candidate promoter region (TSS ± 2 kb) was further divided into 20 consecutive subregions, which were termed ‘bins’. The DNA methylation dynamics of these regions were systematically analysed along with their effects on gene expression in human early embryos. The dynamic DNA methylation subpatterns at the distinct genomic regions with a focus on promoter regions were mapped. For the 12 distinct genomic regions, up2 and 5'UTR had the lowest DNA methylation levels, and their methylation dynamics were different with other regions. The region 3'UTR had the highest DNA methylation levels, and the correlation analysis with gene expression proved that it was a feature of transcribed genes. For the 20 bins in promoter region, the CpG densities showed a normal distribution pattern, and the trend of the methylated CpG counts was inverse with the DNA methylation levels, especially for the bin 1 (downstream 200 bp of the TSS). Through the correlation analysis between DNA methylation and gene expression, the current study finally revealed that the region bin −4 to 6 (800 bp upstream to 1200 bp downstream of the TSS) was the best candidate for the promoter region in human early embryos, and bin 1 was the putative key regulator of gene activity. This study provided a global and high-resolution view of DNA methylation subpatterns at the distinct genomic regions in human early embryos.

Methyl-CpG-binding proteins in cancer: blaming the DNA methylation messenger

2005 ◽  
Vol 83 (3) ◽  
pp. 374-384 ◽  
Author(s):  
Esteban Ballestar ◽  
Manel Esteller
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor Genes ◽  
Binding Proteins ◽  
Excision Repair ◽  
Cpg Islands ◽  
Current Data ◽  
Epigenetic Alterations ◽  
Domain Family ◽  
Promoter Regions ◽  
Cancer Epigenetics

In recent years, epigenetic alterations have come to prominence in cancer research. In particular, hypermethylation of CpG islands located in the promoter regions of tumor-suppressor genes is now firmly established as an important mechanism for gene inactivation in cancer. One of the most remarkable achievements in the field has been the identification of the methyl-CpG-binding domain family of proteins, which provide mechanistic links between specific patterns of DNA methylation and histone modifications. Although many of the current data indicate that methyl-CpG-binding proteins play a key role in maintaining a transcriptionally inactive state of methylated genes, MBD4 is also known to be involved in excision repair of T:G mismatches. The latter is a member of this family of proteins and appears to play a role in reducing mutations at 5-methylcytosine. This review examines the contribution of methyl-CpG-binding proteins in the epigenetic pathway of cancer.Key words: methyl-CpG-binding, MeCP2, DNA methylation, Rett syndrome, cancer epigenetics.

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