scholarly journals Aberrant methylation of multiple imprinted genes in embryos of tamoxifen-treated male rats

Reproduction ◽  
2013 ◽  
Vol 146 (2) ◽  
pp. 155-168 ◽  
Author(s):  
Neelam A Kedia-Mokashi ◽  
Leena Kadam ◽  
Mandar Ankolkar ◽  
Kushaan Dumasia ◽  
N H Balasinor
Keyword(s):  
De Novo ◽  
Methylation Status ◽  
Cpg Islands ◽  
Transcript Level ◽  
Male Rats ◽  
Imprinted Genes ◽  
Aberrant Methylation ◽  
Aberrant Expression ◽  
Treated Male ◽  
Epigenetic Phenomenon

Genomic imprinting is an epigenetic phenomenon known to regulate fetal growth and development. Studies from our laboratory have demonstrated that treatment of adult male rats with tamoxifen increased postimplantation loss around mid gestation. Further studies demonstrated the aberrant expression of transcripts of several imprinted genes in the resorbing embryos at days 11 and 13 of gestation including IGF2. In addition, decreased methylation at theIgf2–H19imprint control region was observed in spermatozoa and in resorbing embryos sired by tamoxifen-treated males. In this study, methylation analysis of the imprinted genes, which were found to be differentially expressed, was done using EpiTYPER in the spermatozoa of tamoxifen-treated rats and in postimplantation embryos sired by tamoxifen-treated rats. Differentially methylated regions (DMRs) for most imprinted genes have not been identified in the rats. Hence, initial experiments were performed to identify the putative DMRs in the genes selected for the study. Increased methylation at CpG islands present in the putative DMRs of a number of imprinted genes was observed in the resorbing embryos sired by tamoxifen-treated male rats. This increase in methylation is associated with the downregulation of most of these genes at the transcript level in resorbing embryos. No change in the methylation status of these genes was observed in spermatozoa. These observations suggest that a deregulation of mechanisms protecting unmethylated alleles from a wave ofde novomethylation occurs following implantation.

Aberrant Genes Promoter Methylation in Neural Crest-Derived Tumors

2012 ◽  
Vol 27 (4) ◽  
pp. 389-394 ◽  
Author(s):  
Annamaria La Torre ◽  
Lucia Anna Muscarella ◽  
Paola Parrella ◽  
Teresa Balsamo ◽  
Michele Bisceglia ◽  
...  
Keyword(s):  
Small Bowel ◽  
Neural Crest ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Cpg Islands ◽  
Aberrant Methylation ◽  
Tumor Type ◽  
Epigenetic Landscape ◽  
Molecular Biomarker

Disturbances in the epigenetic landscape by aberrant methylation of CpG islands can lead to inactivation of cancer-related genes in solid tumors. We analyzed the promoter methylation status of 6 genes previously reported as cancer-specific methylated (MCAM, SSBP2, NISCH, B4GALT1, KIF1A and RASSF1A) in 38 neural crest-derived tumors by quantitative methylation-specific real-time PCR (QMSP). The results demonstrated that the determination of the methylation status of RASSF1A is able to distinguish between normal and tumor samples in cutaneous melanomas, lung carcinoids and small bowel carcinoids. MCAM methylation levels were significantly higher in lung carcinoids tumors (p=0.001), suggesting that this alteration may represent a molecular biomarker in this tumor type.

Intragenic hypomethylation of DNMT3A in patients with myelodysplastic syndrome

2018 ◽  
Vol 56 (3) ◽  
pp. 485-491 ◽  
Author(s):  
Ying-Ying Zhang ◽  
Jing-Dong Zhou ◽  
Dong-Qin Yang ◽  
Pin-Fang He ◽  
Dong-Ming Yao ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Methylation Status ◽  
World Health ◽  
Differentially Methylated Region ◽  
International Prognostic Scoring System ◽  
Aberrant Expression ◽  
Specific Pcr ◽  
Cell Counts

AbstractBackground:DNMT3Ais a DNA methyltransferase that acts inde novomethylation. Aberrant expression ofDNMT3Ahas been reported in several human diseases, including myelodysplastic syndrome (MDS). However, the pattern ofDNMT3Amethylation remains unknown in MDS.Methods:The present study was aimed to investigate the methylation status ofDNMT3Aintragenic differentially methylated region 2 (DMR2) using real-time quantitative methylation-specific PCR and analyze its clinical significance in MDS.Results:Aberrant hypomethylation ofDNMT3Awas found in 57% (51/90) MDS cases. There were no significant differences in age, sex, white blood cell counts, platelet counts, hemoglobin counts and World Health Organization, International Prognostic Scoring System and karyotype classifications betweenDNMT3Ahypomethylated andDNMT3Ahypermethylated groups. However, the patients withDNMT3Ahypomethylation had shorter overall survival time than those withoutDNMT3Ahypomethylation (11 months vs. 36 months, p=0.033). Multivariate analysis confirmed the independent adverse impact ofDNMT3Ahypomethylation in MDS.Conclusions:Our data suggest thatDNMT3ADMR2 hypomethylation may be a negative prognostic hallmark in MDS.

scholarly journals De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase.

1996 ◽  
Vol 16 (8) ◽  
pp. 4555-4565 ◽  
Author(s):  
P M Vertino ◽  
R W Yen ◽  
J Gao ◽  
S B Baylin
Keyword(s):  
Enzyme Activity ◽  
De Novo ◽  
Cpg Island ◽  
Human Fibroblasts ◽  
Methylation Status ◽  
Cpg Islands ◽  
Parental Cell Line ◽  
Direct Role ◽  
Cpg Island Methylation ◽  
De Novo Methylation

Recent studies showing a correlation between the levels of DNA (cytosine-5-)-methyltransferase (DNA MTase) enzyme activity and tumorigenicity have implicated this enzyme in the carcinogenic process. Moreover, hypermethylation of CpG island-containing promoters is associated with the inactivation of genes important to tumor initiation and progression. One proposed role for DNA MTase in tumorigenesis is therefore a direct role in the de novo methylation of these otherwise unmethylated CpG islands. In this study, we sought to determine whether increased levels of DNA MTase could directly affect CpG island methylation. A full-length cDNA for human DNA MTase driven by the cytomegalovirus promoter was constitutively expressed in human fibroblasts. Individual clones derived from cells transfected with DNA MTase (HMT) expressed 1- to 50-fold the level of DNA MTase protein and enzyme activity of the parental cell line or clones transfected with the control vector alone (Neo). To determine the effects of DNA MTase overexpression on CpG island methylation, we examined 12 endogenous CpG island loci in the HMT clones. HMT clones expressing > or = 9-fold the parental levels of DNA MTase activity were significantly hypermethylated relative to at least 11 Neo clones at five CpG island loci. In the HMT clones, methylation reached nearly 100% at susceptible CpG island loci with time in culture. In contrast, there was little change in the methylation status in the Neo clones over the same time frame. Taken together, the data indicate that overexpression of DNA MTase can drive the de novo methylation of susceptible CpG island loci, thus providing support for the idea that DNA MTase can contribute to tumor progression through CpG island methylation-mediated gene inactivation.

Aberrant Expression and Methylation Status of Putatively Imprinted Genes in Placenta of Cloned Piglets

2010 ◽  
Vol 12 (2) ◽  
pp. 213-222 ◽  
Author(s):  
Yanchang Wei ◽  
Jiang Zhu ◽  
Yanjun Huan ◽  
Zhongfeng Liu ◽  
Cairong Yang ◽  
...  
Keyword(s):  
Methylation Status ◽  
Imprinted Genes ◽  
Aberrant Expression

Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 698-700 ◽  
Author(s):  
Maria Teresa Voso ◽  
Alessandra Scardocci ◽  
Francesco Guidi ◽  
Gina Zini ◽  
Antonella Di Mario ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Methylation Status ◽  
Initial Diagnosis ◽  
Early Event ◽  
Aberrant Methylation ◽  
Dap Kinase ◽  
Acute Myeloid

Abstract Death-associated protein kinase (DAP-kinase), a proapoptotic serine/threonine kinase, is a candidate tumor suppressor gene. We studied the methylation status of DAP-kinase of 194 bone marrow samples from 160 patients with acute myeloid leukemia (AML) and 34 with a myelodysplastic syndrome (MDS) at the time of initial diagnosis by polymerase chain reaction (PCR). Hypermethylation of DAP-kinase was present in 27.5% (44 of 160) of AML and in 47% (16 of 34) of MDS specimens and significantly correlated to loss of DAP-kinase expression (P = .008). It was significantly more frequent in AML secondary to therapy for other malignancies (s-AML; 14 of 29, 48.3%), as compared to de novo AML (30 of 131, 22.9%, P = .01). DAP-kinase hypermethylation in AML was associated with myelodysplastic changes in the bone marrow at the time of the initial diagnosis (P = .002) and with the presence of cytogenetic abnormalities (P = .02). Alteration in the apoptotic response due to the loss of DAP-kinase function may be an early event in the transformation pathway to secondary leukemia via myelodysplasia.

Methylation profiling in acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2823-2829 ◽  
Author(s):  
Minoru Toyota ◽  
Kenneth J. Kopecky ◽  
Mutsumi-Ohe Toyota ◽  
Kam-Wing Jair ◽  
Cheryl L. Willman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Correlation Coefficients ◽  
Aberrant Methylation ◽  
Independent Events ◽  
Methylation Defects ◽  
Acute Myeloid

Abstract Aberrant methylation of multiple CpG islands has been described in acute myeloid leukemia (AML), but it is not known whether these are independent events or whether they reflect specific methylation defects in a subset of cases. To study this issue, the methylation status of 14 promoter-associated CpG islands was analyzed in 36 cases of AML previously characterized for estrogen-receptor methylation (ERM). Cases with methylation density of 10% or greater were considered positive. Seventeen cases (47%) were ERM+ while 19 cases were ERM−. Hypermethylation of any of the following,p15, p16, CACNA1G,MINT1, MINT2, MDR1,THBS1, and PTC1 (2 promoters), was relatively infrequent (6% to 31% of patients). For each of these CpG islands, the methylation density was positively correlated with ERM density (rank order correlation coefficients, 0.32-0.59; 2-tailedP ≤ .058 for each gene). Hypermethylation ofMYOD1, PITX2, GPR37, andSDC4 was frequently found in AML (47% to 64% of patients). For each of these genes as well, methylation density was positively correlated with ERM density (correlation coefficients 0.43 to 0.69, P ≤ .0087 for each gene). MLH1 was unmethylated in all cases. Hypermethylation of p15,MDR1, and SDC4 correlated with reduced levels of expression. There was an inverse correlation between age and the number of genes methylated (P = .0030). It was concluded that CpG-island methylation in AML results from methylation defects in subsets of cases. These results have potential implications for the classification and prognosis of AML and for the identification of patients who may benefit from treatment with methylation inhibitors.

Genome-Wide De Novo Methylation in Epithelial Ovarian Cancer

2011 ◽  
Vol 21 (2) ◽  
pp. 269-279 ◽  
Author(s):  
Rachel Michaelson-Cohen ◽  
Ilana Keshet ◽  
Ravid Straussman ◽  
Merav Hecht ◽  
Howard Cedar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Differentiation ◽  
Gene Silencing ◽  
De Novo ◽  
Cpg Islands ◽  
Aberrant Methylation ◽  
Genome Wide ◽  
A Genome ◽  
Treatment Responsiveness ◽  
De Novo Methylation

Background:DNA methylation regulates gene expression during development. The methylation pattern is established at the time of implantation. CpG islands are genome regions usually protected from methylation; however, selected islands are methylated later. Many undergo methylation in cancer, causing epigenetic gene silencing. Aberrant methylation occurs early in tumorigenesis, in a specific pattern, inhibiting differentiation.Although methylation of specific genes in ovarian tumors has been demonstrated in numerous studies, they represent only a fraction of all methylated genes in tumorigenesis.Objectives:To explore the hypermethylation design in ovarian cancer compared with the methylation profile of normal ovaries, on a genome-wide scale, thus shedding light on the role of gene silencing in ovarian carcinogenesis.Identifying genes that undergo de novo methylation in ovarian cancer may assist in creating biomarkers for disease diagnosis, prognosis, and treatment responsiveness.Methods:DNA was collected from human epithelial ovarian cancers and normal ovaries. Methylation was detected by immunoprecipitation using 5-methyl-cytosine-antibodies. DNA was hybridized to a CpG island microarray containing 237,220 gene promoter probes. Results were analyzed by hybridization intensity, validated by bisulfite analysis.Results:A total of 367 CpG islands were specifically methylated in cancer cells. There was enrichment of methylated genes in functional categories related to cell differentiation and proliferation inhibition. It seems that their silencing enables tumor proliferation.Conclusions:This study provides new perspectives on methylation in ovarian carcinoma, genome-wide. It illustrates how methylation of CpG islands causes silencing of genes that have a role in cell differentiation and functioning. It creates potential biomarkers for diagnosis, prognosis, and treatment responsiveness.

scholarly journals Hypermethylation of the p15INK4B Gene in Myelodysplastic Syndromes

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1403-1409 ◽  
Author(s):  
Toshiki Uchida ◽  
Tomohiro Kinoshita ◽  
Hirokazu Nagai ◽  
Yohsuke Nakahara ◽  
Hidehiko Saito ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Malignant Tumors ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Hematologic Malignancies ◽  
Genetic Alterations ◽  
Refractory Anemia ◽  
Aberrant Methylation ◽  
Cyclin Dependent Kinase Inhibitor

Previous studies have shown that the cyclin-dependent kinase inhibitor (CDKI) genes p15INK4B and p16INK4A are frequently inactivated by genetic alterations in many malignant tumors and that they are candidate tumor-suppressor genes. Although genetic alterations in these genes may be limited to lymphoid malignancies, it has been reported that their inactivation by aberrant methylation of 5′ CpG islands may be involved in various hematologic malignancies. In this study, we investigated the p15INK4B and p16INK4A genes to clarify their roles in the pathogenesis of myelodysplastic syndrome (MDS). Southern blotting analysis showed no gross genetic alterations in either of these genes. However, hypermethylation of the 5′ CpG island of the p15INK4B gene occurred frequently in patients with MDS (16/32 [50%]). Interestingly, the p15INK4B gene was frequently methylated in patients with high-risk MDS (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-t], and overt leukemia evolved from MDS; 14/18 [78%]) compared with patients with low-risk MDS (refractory anemia [RA] and refractory anemia with ring sideroblast [RARS]; 1/12 [8%]). Furthermore, methylation status of the p15INK4B gene was progressed with the development of MDS in most patients examined. In contrast, none of the MDS patients showed apparent hypermethylation of the p16INK4A gene. These results suggest that hypermethylation of the p15INK4B gene is involved in the pathogenesis of MDS and is one of the important late events during the development of MDS.

scholarly journals Long-Term Disturbed Expression and DNA Methylation of SCAP/SREBP Signaling in the Mouse Lung From Assisted Reproductive Technologies

2021 ◽  
Vol 12 ◽  
Author(s):  
Fang Le ◽  
Ning Wang ◽  
Qijing Wang ◽  
Xinyun Yang ◽  
Lejun Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Assisted Reproductive Technologies ◽  
Methylation Status ◽  
Reproductive Technologies ◽  
Mouse Lung ◽  
Aberrant Methylation ◽  
Aberrant Expression ◽  
Expression Levels

Assisted reproductive technology (ART) has been linked to cholesterol metabolic and respiratory disorders later in life, but the mechanisms by which biosynthetic signaling remain unclear. Lung inflammatory diseases are tightly linked with the sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP), but this has not been shown in an ART offspring. Here, mouse models from a young to old age were established including in vitro fertilization (IVF), intracytoplasmic injection (ICSI), and in vivo fertilized groups. In our results, significantly higher plasma levels of CRP, IgM, and IgG were identified in the aged ICSI mice. Additionally, pulmonary inflammation was found in four aged ART mice. At three weeks, ART mice showed significantly downregulated levels of Scap, Srebp-1a, Srebp-1c, and Srebf2 mRNA in the lung. At the same time, significant differences in the DNA methylation rates of Scap-Srebfs and protein expression of nuclear forms of SREBPs (nSREBPs) were detected in the ART groups. Only abnormalities in the expression levels of Srebp-1a and Srebp-1c mRNA and nSREBP1 protein were found in the ART groups at 10 weeks. However, at 1.5 years old, aberrant expression levels and DNA methylation of SCAP, SREBP1, and SREBP2, and their associated target genes, were observed in the lung of the ART groups. Our results indicate that ART increases long-term alterations in SCAP/SREBP expression that may be associated with their aberrant methylation status in mouse.

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