scholarly journals LINE-1 Hypomethylation in a Choline-Deficiency-Induced Liver Cancer in Rats: Dependence on Feeding Period

2006 ◽  
Vol 2006 ◽  
pp. 1-6 ◽  
Author(s):  
Kiyoshi Asada ◽  
Yashige Kotake ◽  
Rumiko Asada ◽  
Deborah Saunders ◽  
Robert H. Broyles ◽  
...  
Keyword(s):  
Cytosine Methylation ◽  
Methylation Status ◽  
Repetitive Sequences ◽  
Cpg Islands ◽  
Surrogate Marker ◽  
Surrounding Tissue ◽  
Feeding Time ◽  
Aberrant Methylation ◽  
Deficient Diet ◽  
Methyl Donor

Chronic feeding of methyl-donor (methionine, choline, folic acid, and vitamin B12) deficient diet induces hepatocellular carcinoma formation in rats. Previous studies have shown that promoter CpG islands in various cancer-related genes are aberrantly methylated in this model. Moreover, the global genome in methyl-donor-deficient diet fed rats contains a lesser amount of 5-methylcytosine than control livers. It is speculated that more than 90% of all 5-methylcytosines lie within the CpG islands of the transposons, including the long/short interspersed nucleotide elements (LINE and SINE). It is considered that the 5-methylcytosines in LINE-1 limit the ability of retrotransposons to be activated and transcribed; therefore, the extent of hypomethylation of LINE-1 could be a surrogate marker for aberrant methylation in other tumor-related genes as well as genome instability. Additionally, LINE-1 methylation status has been shown to be a good indicator of genome-wide methylation. In this study, we determined cytosine methylation status in the LINE-1 repetitive sequences of rats fed a choline-deficient (CD) diet for various durations and compared these with rats fed a choline-sufficient (CS) diet. The methylation status of LINE-1 was assessed by the combined bisulfite restriction analysis (COBRA) method, where the amount of bisulfite-modified and RsaI-cleaved DNA was quantified using gel electrophoresis. Progressive hypomethylation was observed in LINE-1 of CD livers as a function of feeding time; that is, the amount of cytosine in total cytosine (methylated and unmethylated) increased from 11.1% (1 week) to 19.3% (56 weeks), whereas in the control CS livers, it increased from 9.2% to 12.9%. Hypomethylation in tumor tissues was slightly higher (6%) than the nontumorous surrounding tissue. The present result also indicates that age is a factor influencing the extent of cytosine methylation.

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.

scholarly journals Maternal Melatonin Therapy Attenuates Methyl-Donor Diet-Induced Programmed Hypertension in Male Adult Rat Offspring

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1407 ◽  
Author(s):  
You-Lin Tain ◽  
Julie Chan ◽  
Chien-Te Lee ◽  
Chien-Ning Hsu
Keyword(s):  
Methylation Status ◽  
Normal Diet ◽  
Male Offspring ◽  
Adult Offspring ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Deficient Diet ◽  
Male Adult ◽  
Methyl Donor ◽  
Adult Rat

Although pregnant women are advised to consume methyl-donor food, some reports suggest an adverse outcome. We investigated whether maternal melatonin therapy can prevent hypertension induced by a high methyl-donor diet. Female Sprague-Dawley rats received either a normal diet, a methyl-deficient diet (L-MD), or a high methyl-donor diet (H-MD) during gestation and lactation. Male offspring were assigned to four groups (n = 7–8/group): control, L-MD, H-MD, and H-MD rats were given melatonin (100 mg/L) with their drinking water throughout the period of pregnancy and lactation (H-MD+M). At 12 weeks of age, male offspring exposed to a L-MD or a H-MD diet developed programmed hypertension. Maternal melatonin therapy attenuated high methyl-donor diet-induced programmed hypertension. A maternal L-MD diet and H-MD diet caused respectively 938 and 806 renal transcripts to be modified in adult offspring. The protective effects of melatonin against programmed hypertension relate to reduced oxidative stress, increased urinary NO2− level, and reduced renal expression of sodium transporters. A H-MD or L-MD diet may upset the balance of methylation status, leading to alterations of renal transcriptome and programmed hypertension. A better understanding of reprogramming effects of melatonin might aid in developing a therapeutic strategy for the prevention of hypertension in adult offspring exposed to an excessive maternal methyl-supplemented diet.

Epigenetic Dysregulation of Candidate Cis-Regulatory Sequences in Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2229-2229
Author(s):  
Reid F. Thompson ◽  
Maria E. Figueroa ◽  
Ari M. Melnick ◽  
John M. Greally
Keyword(s):  
Cytosine Methylation ◽  
Hematological Malignancies ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Regulatory Sequences ◽  
Cpg Island Methylator Phenotype ◽  
Global Methylation ◽  
Methylator Phenotype ◽  
Tumor Types

Abstract Epigenetic changes (in particular, altered cytosine methylation) have been described in a variety of tumors. The CpG Island Methylator Phenotype (CIMP) is a well-known instance of this phenomenon wherein cytosine methylation is markedly dysregulated (normally hypomethylated loci shift to a methylated state). CIMP has been demonstrated in a number of different cancer types including hematological malignancies like AML. While methylation status has been studied predominantly at CpG islands, we used a novel assay (HELP; Khulan et al., Genome Res. 2006) to look for changes in cytosine methylation in large contiguous regions of the genome. We assessed global patterns of cytosine methylation by HELP analysis in a variety of tumor samples including leukemias and lymphomas. We found significant changes in the global methylation patterns of malignant cells, confirming prior observations of epigenetic dysregulation in these tumor types. We also discovered that the majority of the changes in cytosine methylation are occurring not at CpG islands but at other loci in the genome, including constitutively hypomethylated loci that we are finding to be candidate cis-regulatory sequences. We conclude that cytosine methylation changes in cancer occur much more extensively than analysis of CpG islands alone would indicate, and that the epigenetic dysregulation in cancer may be predominantly targeted to cis-regulatory sequences rather than to promoters.

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.

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.

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.

Epigenetic Inactivation of the Secreted Frizzled-Related Protein Gene Family in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2131-2131
Author(s):  
Edgar Jost ◽  
Deniz Gezer ◽  
Stefan Wilop ◽  
James G. Herman ◽  
Rainhardt Osieka ◽  
...  
Keyword(s):  
Cell Lines ◽  
Wnt Pathway ◽  
Methylation Status ◽  
Cpg Islands ◽  
Promoter Hypermethylation ◽  
Aberrant Methylation ◽  
Chain Reaction ◽  
Genetic Aberrations ◽  
Polymerase Chain

Abstract Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the accumulation of malignant plasma cells in the bone marrow. Previous molecular studies have largely focused on acquired genetic aberrations in MM. There is increasing evidence that in addition to genetic aberrations epigenetic processes play a major role in carcinogenesis. Aberrant methylation of CpG islands near gene promoter regions is the most widely studied epigenetic abnormality in human malignancies and is associated with loss of gene function. This epigenetic event acts as an alternative to mutations and deletions to disrupt tumor suppressor gene function. The Wnt pathway has been recognized to be essential for normal organ development, and a role for Wnt signal transduction at several stages of lymphocyte differentiation and in the self-renewal of hematopoietic stem cells could be demonstrated. Alterations in the Wnt pathway have been shown to contribute to the pathogenesis of various human malignancies. Epigenetic silencing of the family of secreted frizzled-related proteins (SFRPs), which act as Wnt antagonists, was recently reported in several solid tumors and in acute lymphoblastic leukemia. In order to investigate the potential role of abnormal Wnt signaling in MM, we determined the methylation status of the promoter-associated CpG islands of SFRP-1, 2, 4 and 5 in the MM cell lines U266, LP-1, RPMI-8226 and OPM-2. Methylation-specific polymerase chain reaction (MSP) analysis revealed that promoter hypermethylation of the SFRP genes was a frequent event in MM cell lines (SFRP-1: 2/4, SFRP-2: 2/4, SFRP-4: 1/4 and SFRP-5: 3/4). Aberrant methylation of SFRP-1 and SFRP-2 in MM cell lines was associated with transcriptional silencing, as determined by real-time reverse transcriptase polymerase chain reaction. Treatment of cell lines that carry a hypermethylated SFRP-1 and SFRP-2 gene, respectively, with the demethylating agent 5-aza-2′-deoxycytidine resulted in gene reexpression. We then analyzed by MSP the methylation status of SFRP-1, 2, 4 and 5 in 76 specimens obtained from MM patients. The frequency of aberrant methylation among the primary patient samples was 38.2% (29/76) for SFRP-1, 59.2% (45/76) for SFRP-2, 2.6% (2/76) for SFRP-4 and 7.6% (6/76) for SFRP-5. There was a high incidence of concomitant hypermethylation of SFRP-1 and SRFP-2. We conclude that promoter hypermethylation of the SFRP genes is a novel epigenetic event in MM that may contribute to aberrant activation of the Wnt pathway. Further studies are warranted to elucidate the functional consequences of aberrant Wnt signaling by downregulation of the SFRP genes in the pathogenesis of MM. Additionally, the increasing evidence for the important role of DNA methylation changes in malignant plasma cell disorders may serve as a basis for the use of epigenetically targeted therapeutic approaches in MM in the future.

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

Abstract 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 In Vivo and In Vitro Assays Evaluating the Biological Activity of Taurine, Glucose and Energetic Beverages

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2198
Author(s):  
Marcos Mateo-Fernández ◽  
Fernando Valenzuela-Gómez ◽  
Rafael Font ◽  
Mercedes Del Río-Celestino ◽  
Tania Merinas-Amo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Drosophila Melanogaster ◽  
Biological Activity ◽  
Biological Effects ◽  
Methylation Status ◽  
Repetitive Sequences ◽  
Energy Drinks ◽  
Red Bull

Taurine is one of the main ingredients used in energy drinks which are highly consumed in adolescents for their sugary taste and stimulating effect. With energy drinks becoming a worldwide phenomenon, the biological effects of these beverages must be evaluated in order to fully comprehend the potential impact of these products on the health due to the fact nutrition is closely related to science since the population consumes food to prevent certain diseases. Therefore, the aim of this study was to evaluate the biological effects of taurine, glucose, classic Red Bull® and sugar-free Red Bull® in order to check the food safety and the nutraceutical potential of these compounds, characterising different endpoints: (i) Toxicology, antitoxicology, genotoxicology and life expectancy assays were performed in the Drosophila melanogaster model organism; (ii) The in vitro chemopreventive activity of testing compounds was determined by assessing their cytotoxicity, the proapoptotic DNA-damage capability to induce internucleosomal fragmentation, the strand breaks activity and the modulator role on the methylation status of genomic repetitive sequences of HL-60 promyelocytic cells. Whereas none tested compounds showed toxic or genotoxic effect, all tested compounds exerted antitoxic and antigenotoxic activity in Drosophila. Glucose, classic Red Bull® and sugar-free Red Bull® were cytotoxic in HL-60 cell line. Classic Red Bull® induced DNA internucleosomal fragmentation although none of them exhibited DNA damage on human leukaemia cells. In conclusion, the tested compounds are safe on Drosophila melanogaster and classic Red Bull® could overall possess nutraceutical potential in the in vivo and in vitro model used in this study. Besides, taurine could holistically be one of the bioactive compounds responsible for the biological activity of classic Red Bull®.

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