scholarly journals Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro-opiomelanocortin gene

2011 ◽  
Vol 106 (5) ◽  
pp. 769-778 ◽  
Author(s):  
M. Palou ◽  
Catalina Picó ◽  
J. A. McKay ◽  
J. Sánchez ◽  
T. Priego ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Leptin Receptor ◽  
Methylation Status ◽  
Male Rats ◽  
Mrna Levels ◽  
Protective Effects ◽  
Suckling Period ◽  
Promoter Regions ◽  
Weak Negative Correlation ◽  
Physiological Dose

Leptin supplementation of neonatal rats during the suckling period protects against being overweight in adulthood and ameliorates the control of food intake. This was associated with changes in the expression of hypothalamic genes involved in the central action of leptin: pro-opiomelanocortin (Pomc), leptin receptor (Lepr) and suppressor of cytokine signalling (Socs3). The purpose of the present study was to determine the methylation status within the promoter regions of these genes and to assess whether the observed changes in the expression levels of these genes could be explained by changes in their methylation status. Male rats were treated daily with an oral physiological dose of leptin or vehicle during the suckling period. After weaning, animals were fed with a normal-fat or a high-fat (HF) diet until aged 6 months. DNA was extracted from the hypothalamus and methylation within the promoter regions of the gene panel was measured by pyrosequencing. Pomc promoter methylation increased in control animals fed the HF diet but decreased in leptin-treated animals. In addition, there was a weak negative correlation between DNA methylation and POMC mRNA levels (P = 0·075). There were no changes in the methylation status of the CpG sites studied within the promoter regions of Lepr and Socs3 in response to leptin or HF treatments. This is the first demonstration that leptin treatment during lactation may programme methylation of an appetite-related gene in the hypothalamus of animals fed HF diets, with possible implications for gene expression and protection against the development of obesity.

scholarly journals Leptin and glucocorticoid signaling pathways in the hypothalamus of female and male fructose-fed rats

2014 ◽  
Vol 66 (2) ◽  
pp. 829-839 ◽  
Author(s):  
Danijela Vojnovic-Milutinovic ◽  
Marina Nikolic ◽  
Jovana Dinic ◽  
Ana Djordjevic ◽  
Natasa Velickovic ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Leptin Receptor ◽  
Female Rats ◽  
Male Rats ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Leptin Sensitivity ◽  
Male And Female Rats ◽  
Glucocorticoid Signaling

Alterations in leptin and glucocorticoid signaling pathways in the hypothalamus of male and female rats subjected to a fructose-enriched diet were studied. The level of expression of the key components of the leptin signaling pathway (neuropeptide Y /NPY/ and suppressor of cytokine signaling 3 /SOCS3/), and the glucocorticoid signaling pathway (glucocorticoid receptor /GR/, 11?-hydroxysteroid dehydrogenase type 1 /11?HSD1/ and hexose-6-phosphate dehydrogenase /H6PDH/) did not differ between fructose-fed rats and control animals of both genders. However, in females, a fructose-enriched diet provoked increases in the adiposity index, plasma leptin and triglyceride concentrations, and displayed a tendency to decrease the leptin receptor (ObRb) protein and mRNA levels. In male rats, the fructose diet caused elevations in plasma non-esterified fatty acids and triglycerides, as well as in both plasma and hypothalamic leptin concentrations. Our results suggest that a fructose-enriched diet can induce hyperleptinemia in both female and male rats, but with a more pronounced effect on hypothalamic leptin sensitivity in females, probably contributing to the observed development of visceral adiposity.

Promoter Methylation and Decreased Expression of Mir-124 In Myelodysplastic Syndromes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4014-4014
Author(s):  
Yuesheng Meng ◽  
Qiao Xia ◽  
Jun Hu
Keyword(s):  
Myelodysplastic Syndromes ◽  
Promoter Methylation ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Quantitative Polymerase Chain Reaction ◽  
Methylation Status ◽  
Polymerase Chain Reaction Analysis ◽  
Promoter Regions ◽  
Hematopoietic Stem

Abstract Abstract 4014 The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of hematopoietic stem/progenitor cells. Although demethylating agents such azacytidine and decitabine have been widely used to treat MDS, the underlying molecular mechanisms remain obscure. Abnormalities of microRNAs (miRNA) have been recently associated with hematological malignancies including MDS. The miR-124 was initially demonstrated to modulate neurogenesis. It was recently shown that EVI1-induced methylation and silencing of miR-124 were present in murine MDS cells. In the retrospective study we evaluated methylation status and expression levels of miR-124 in fifteen MDS patients (subtypes included RCUD, RCMD, RAEB-1, RAEB-2 and CMML). Genomic DNA samples were modified with bisulfite and methylation at three promoter regions of miR-124 was examined with methylation-specific real time quantitative polymerase chain reaction analysis (MQPCR). In general, we observed an increased methylation levels of miR-124 in MDS patients than that in normal bone marrow (NBM, P<0.01). In accordance with this, marked depression of miR-124 was seen in six patients when compared with NBM (more than 2 times lower), as determined with quantitative reverse-transcriptive PCR assay. Moreover, there were higher degrees of promoter methylation in cases with depressed miR-124 than that in remaining cases. A negative correlation between the expression and methylation levels was statistically significant (R= -0.498, P<0.01). The change of miR-124 was not directly related to short-term clinical response or prognosis, possibly due to limited size of the sample. However, the miR-124 amount returned to basal levels in two cases (RCMD and CMML subtypes respectively) after low-dose decitabine therapy and DNA methylation of all three loci disappeared. Continued work is underway to accumulate more cases and make long-term clinical follow-up. In conclusion, this primary work suggested a possible role of the methylation-mediated silencing of miR-124 in the pathogenesis or disease progression of MDS. Disclosures: No relevant conflicts of interest to declare.

Title: Promoter Methylation of Selected Genes and Response to Azacitidine (AZ) Therapy in Patients with Non-BCR-ABL Myeloproliferative Disorders (MPDs)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4625-4625
Author(s):  
Nicholas Achille ◽  
Laura Michaelis ◽  
Scott E. Smith ◽  
Eliza Germano ◽  
Nancy J. Zeleznik-Le ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
Research Funding ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Cpg Islands ◽  
Myeloproliferative Disorders ◽  
Response To Treatment ◽  
Promoter Regions ◽  
Days Of Therapy

Abstract Abstract 4625 Background: Gene silencing via methylation of CpG islands in the promoter regions of many genes but specifically of APAF1, p15INK4B, p16INK4A, RARB, and CDH1 appears to play a role in pathogenesis of myeloid malignancies. Azacitidine (AZ) causes demethylation by inhibiting DNA methyltransferase and has already been shown to be an effective therapy for myelodysplastic syndromes. The demethylation induced by AZ is detectable in about 48 hours and increases significantly after 5 days of therapy. After that, the effect tends to plateau. Methods: We initiated a Phase 2 study of patients with non-BCR-ABL MPDs to determine clinical response to AZ therapy and correlate it with promoter DNA methylation and gene re-expression. The protocol was approved by the institutional IRB. Patients received AZ 75mg/m2 s/c for days 1–7 and repeated every 28 days for a minimum of 4 cycles. Responders were allowed to continue treatment until disease progression. Pretreatment and D 7 peripheral blood samples were analyzed for promoter methylation status and expression of the 5 genes mentioned above. Bisulfite conversion of DNA was followed by quantitative PCR using primers specific for methylated or for unmethylated promoter regions. For gene re-expression analysis, quantitative RT-PCR was performed with RNA isolated from the same patient samples and the same time points as the DNA methylation analyses. Results: Seven patients were enrolled before the study closed due to lack of accrual. The diagnoses were: Myelofibrosis (MF) 4, essential thrombocythemia 1, unclassified MPD with dysplasia 2. One patient with MF and one with unclassified MPD responded, the latter with normalization of marrow karyotype. Both responses were accompanied by significant decrease in APAF1 promoter methylation and surprisingly, an increase in promoter methylation of RARB. In three of the non-responders, APAF1 methylation increased. In patients with decreased Apaf1 methylation, a statistically significant increase in mRNA expression was observed. Conclusions: Within its limitations, this small trial shows that the methylation status of selected genes, particularly of APAF1 and RARB (inversely) is associated with response to treatment with azacitidine in patients with MPDs. In non-responders, Apaf1 methylation appears to increase. A larger study will be necessary to confirm these preliminary observations. Disclosures: Smith: Seattle Genetics, Inc.: Research Funding; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy; GSK: Speakers Bureau. Nand:Celgene Corporation: Research Funding.

Regulation of the EGFR-E2F3a axis by the interferon regulatory factor (IRFs) and by promoter methylation of miR-34a in ovarian cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16522-e16522
Author(s):  
D. Reimer ◽  
M. Hubalek ◽  
S. Riedle ◽  
S. Skvortsov ◽  
M. Erdel ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Family Members ◽  
Alternative Mechanism ◽  
Mrna Levels ◽  
Knock Down ◽  
Egfr Activation

e16522 Background: Although, EGFR targeting has reached “bedside” in various tumor entities, including ovarian cancer, the essential role of E2F3a in EGFR mediated proliferation remained uncovered. Recently, we outlined the clinical relevance of E2F3a in ovarian cancer. Now we were able to elucidate the pathway between EGFR activation and E2F3a induction. Methods: Promoter mapping of E2F family members was assessed using the JASPER software. E2F3a protein was assessed by immunoblot analyses in siRNA based IRF-1, IRF-2 knockdown HOC-7 cells. Cell growth was determined by MTT assays after siRNA based knockdown of E2F3a. Expression of E2F3a regulating miR-34a, miR-210 and miR-20a were assessed by RT-PCR in 130 ovarian cancer patients and methylation status of the E2F3a promoter and of miRNA promoters were estimated using Methyllight. 6p22 amplification status of patients was determined by FISH analyses. Results: Promoter mapping of E2F family members revealed that IRF-1 and IRF-2 are potential intermediate components of the herein described EGFR-E2F3a axis. As evidenced by knock-down of IRF-1, IRF-2 or both, the ratio between the two mutually antagonistic IRF-1 and IRF-2 was found to be substantial for EGF induced E2F3a up-regulation. E2F3a knock-down yielded a complete abolishment of EGF induced cancer cell proliferation. Although, activated EGFR status showed a highly significant correlation with E2F3a expression, a subgroup of patients presented high E2F3a mRNA levels without EGFR activation. Within this subgroup promoter methylation of miRNA-34a, that regulates E2F3a, was revealed to represent an alternative mechanism of E2F3a regulation in ovarian cancer, whereas promoter methylation of E2F3a itself was not relevant in E2F3a control. Unlike in prostate or bladder cancer 6p22 amplification was not found to be relevant for E2F3a up-regulation in ovarian cancer. Conclusions: Our present data point to the substantial role of the ratio between IRF-1 and IRF-2 in EGFR mediated E2F3a induction. Furthermore, in vivo regulation of E2F3a involves methylation and thereby silencing of miR-34a. Targeting of the herein described molecular pathway, downstream EGFR, could represent an appealing therapeutic approach in ovarian cancer. No significant financial relationships to disclose.

Prenatal famine exposure, health in later life and promoter methylation of four candidate genes

2012 ◽  
Vol 3 (6) ◽  
pp. 450-457 ◽  
Author(s):  
M. V. Veenendaal ◽  
P. M. Costello ◽  
K. A. Lillycrop ◽  
S. R. de Rooij ◽  
J. A. van der Post ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Promoter Methylation ◽  
Peripheral Blood ◽  
Methylation Status ◽  
Later Life ◽  
Proximal Promoter ◽  
Promoter Regions ◽  
Increased Risk ◽  
Famine Exposure ◽  
Prenatal Famine

Poor nutrition during fetal development can permanently alter growth, cardiovascular physiology and metabolic function. Animal studies have shown that prenatal undernutrition followed by balanced postnatal nutrition alters deoxyribonucleic acid (DNA) methylation of gene promoter regions of candidate metabolic control genes in the liver. The aim of this study was to investigate whether methylation status of the proximal promoter regions of four candidate genes differed between individuals exposed to the Dutch famine in utero. In addition, we determined whether methylation status of these genes was associated with markers of metabolic and cardiovascular disease and adult lifestyle. Methylation status of the GR1-C (glucocorticoid receptor), PPARγ (peroxisome proliferator-activated receptor gamma), lipoprotein lipase and phosphatidylinositol 3 kinase p85 proximal promoters was investigated in DNA isolated from peripheral blood samples of 759 58-year-old subjects born around the time of the 1944–45 Dutch famine. We observed no differences in methylation levels of the promoters between exposed and unexposed men and women. Methylation status of PPARγ was associated with levels of high-density lipoprotein cholesterol and triglycerides as well as with exercise and smoking. Hypomethylation of the GR promoter was associated with adverse adult lifestyle factors, including higher body mass index, less exercise and more smoking. The previously reported increased risk of cardiovascular and metabolic disease after prenatal famine exposure was not associated with differences in methylation status across the promoter regions of these candidate genes measured in peripheral blood. The adult environment seems to affect GR and PPARγ promoter methylation.

scholarly journals FHIT promoter methylation status, low protein and high mRNA levels in patients with non-small cell lung cancer

2016 ◽  
Vol 49 (3) ◽  
pp. 1175-1184 ◽  
Author(s):  
Karolina H. Czarnecka ◽  
Monika Migdalska-Sęk ◽  
Daria Domańska ◽  
Dorota Pastuszak-Lewandoska ◽  
Agata Dutkowska ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Small Cell ◽  
Mrna Levels ◽  
Small Cell Lung ◽  
Promoter Methylation Status ◽  
Low Protein

scholarly journals Leptin Signaling in the Hypothalamus during Chronic Central Leptin Infusion

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3789-3798 ◽  
Author(s):  
Rekha Pal ◽  
Abhiram Sahu
Keyword(s):  
Food Intake ◽  
Leptin Receptor ◽  
Binding Activity ◽  
Janus Kinase ◽  
Male Rats ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Leptin Signaling ◽  
Initial Decrease

Abstract Using a rat model of chronic central leptin infusion in which neuropeptide Y neurons develop leptin resistance, we examined whether leptin signal transduction mechanism in the hypothalamus is altered during central leptin infusion. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or vehicle via Alzet pumps for 16 d. In the leptin-infused group, the initial decrease in food intake was followed by a recovery to their preleptin levels by d 16, although food intake remained significantly lower than in artificial cerebrospinal fluid controls; and body weight gradually decreased reaching a nadir at d 11 and remained stabilized at lower level thereafter. Phosphorylated leptin receptor and phosphorylated signal transducer and activator of transcription-3 (p-STAT3) remained elevated in association with a sustained elevation in DNA-binding activity of STAT3 in the hypothalamus throughout 16-d period of leptin infusion. However, phosphorylated Janus kinase-2 was increased during the early part of leptin infusion but remained unaltered on d 16. Although hypothalamic suppressors of cytokine signaling-3 (SOCS3) mRNA levels were increased throughout leptin infusion, SOCS3 protein levels were increased only on d 16. This study demonstrates a sustained elevation in hypothalamic leptin receptor signaling through Janus kinase-STAT pathway despite an increased expression of SOCS3 during chronic central leptin infusion. We propose that an alteration in leptin signaling in the hypothalamus through pathways other than STAT3 and/or a defect in downstream of STAT3 signaling may be involved in food intake recovery seen after an initial decrease during chronic central leptin infusion.

scholarly journals Alterations of the Immunologic Co-Stimulator B7 and TNFR Families Correlate with Hepatocellular Carcinoma Prognosis and Metastasis by Inactivating STAT3

2019 ◽  
Vol 20 (1) ◽  
pp. 156 ◽  
Author(s):  
Yi-Ming Li ◽  
Zhen-Yu Liu ◽  
Zhu-Chun Li ◽  
Jian-Chao Wang ◽  
Jing-Min Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Promoter Methylation ◽  
Critical Role ◽  
Methylation Status ◽  
Gene Copy ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Hcc Cells

Blockade of the immunosuppressive checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed death 1 (PD-1) and its cognate ligand, programmed death 1 ligand (PD-L1), has altered the landscape of anti-tumor immunotherapy. B7 family and tumor necrosis factor receptor (TNFR) superfamily play a crucial role in T cell activation, tolerance, and anergy through co-stimulatory and inhibitory signal transduction. Investigating the immune molecular landscapes of the B7 and TNFR families is critical in defining the promising responsive candidates. Herein, we performed comprehensive alteration analysis of the B7 and TNFR family genes across six hepatocellular carcinoma (HCC) datasets with over 1000 patients using cBioPortal TCGA data. About 16% of patients had both B7 and TNFR gene alterations. TNFR gene amplifications were relatively more common (1.73–8.82%) than B7 gene amplifications (1.61–2.94%). Analysis of 371 sequenced samples revealed that all genes were upregulated: B7 and TNFR mRNA were upregulated in 23% of cases (86/371) and 28% of cases (105/371), respectively. Promoter methylation analysis indicated an epigenetic basis for B7 and TNFR gene regulation. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. B7-H6 expression was significantly associated with worse overall survival, and B7-H6 mRNA was increased gradually in cases with gene copy number alterations. B7-H6 overexpression was associated with aggressive clinicopathologic features and poor prognosis in HCC. Downregulation of B7-H6 in HCC cells significantly inhibited cell adhesion, proliferation, migration, and invasion. Knockdown of B7-H6 in HCC cells inhibited tumor growth and metastasis in vivo. B7-H6 promoted HCC metastasis via induction of MMP-9 expression and STAT3 activation. B7-H6 and STAT3 performed functional overlapping roles on enhancing the MMP-9 promoter activity in HCC cells. These results suggest that alterations of the immunologic co-stimulator B7 and TNFR families correlate with HCC metastasis and prognosis, and especially B7-H6 plays a critical role in promoting metastasis of HCC.

Physiological regulation of hypothalamic IL-1β gene expression by leptin and glucocorticoids: implications for energy homeostasis

2004 ◽  
Vol 287 (6) ◽  
pp. E1107-E1113 ◽  
Author(s):  
Brent E. Wisse ◽  
Kayoko Ogimoto ◽  
Gregory J. Morton ◽  
Charles W. Wilkinson ◽  
R. Scott Frayo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Physiological Role ◽  
Zucker Rats ◽  
Mrna Levels ◽  
Subcutaneous Infusion ◽  
Physiological Regulation ◽  
Physiological Dose ◽  
Opposing Effects

Interleukin-1β (IL-1β) is synthesized in a variety of tissues, including the hypothalamus, where it is implicated in the control of food intake. The current studies were undertaken to investigate whether hypothalamic IL-1β gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1β mRNA levels twofold, measured by real-time PCR ( P < 0.05 vs. sham-operated controls), and this effect was blocked by subcutaneous infusion of a physiological dose of corticosterone. Conversely, hypothalamic IL-1β mRNA levels were reduced by 30% in fa/fa (Zucker) rats, a model of genetic obesity caused by leptin receptor mutation ( P = 0.01 vs. lean littermates), and the effect of ADX to increase hypothalamic IL-1β mRNA levels in fa/fa rats ( P = 0.02) is similar to that seen in normal animals. Moreover, fasting for 48 h (which lowers leptin and raises corticosterone levels) reduced hypothalamic IL-1β mRNA levels by 30% ( P = 0.02), and this decrease was fully reversed by refeeding for 12 h. Thus leptin and GCs exert opposing effects on hypothalamic IL-1β gene expression, and corticosterone plays a physiological role to limit expression of this cytokine in both the presence and absence of intact leptin signaling. Consistent with this hypothesis, systemic leptin administration to normal rats (2 mg/kg ip) increased hypothalamic IL-1β mRNA levels twofold ( P < 0.05 vs. vehicle), an effect similar to that of ADX. These data support a model in which expression of hypothalamic IL-1β is subject to opposing physiological regulation by corticosterone and leptin.

Delineation of Promoter Methylation in Patients with Myelodysplastic Syndromes: Widespread and Concurrent Hypermethylation of Multiple Genes and Increased mRNA Expression of the DNA Methyltransferases DNMT1, 3A and 3B.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 472-472
Author(s):  
Anni Aggerholm ◽  
Mette S. Holm ◽  
Per Guldberg ◽  
Peter Hokland
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Dna Methyltransferases ◽  
Aberrant Methylation ◽  
Mrna Levels ◽  
Over Time

Abstract Transcriptional silencing of tumor suppressor genes by promoter hypermethylation is associated with hematological malignancy, including myelodysplastic syndromes (MDS). Specifically, hypermethylation of the p15 gene has previously been associated with MDS and seems to be acquired with disease progression. The methylation status of other genes associated with the development of myeloid malignancies is, however, largely unknown. We have elucidated this in total bone marrow mononuclear cells (BM-MNC) as well as CD34 enriched cells from 17 patients with different stages of MDS by determining the promoter methylation status in four genes believed to be associated with the development of acute myeloid leukemia (AML), namely those encoding for the p15, HIC, E-cadherin (ECAD), and the Estrogen receptor (ER). Employing Bisulfite-Denaturing Gradient Gel Electrophoresis (Bisulfite-DGGE) we found all four genes to be hypermethylated in MDS, albeit with varying frequencies (19/37, 12/37, 10/37, and 7/37, respectively). Since the Bisulfite-DGGE allows for the detection of heterogeneous methylation patterns we were able to compare these patterns. Similar Bisulfite-DGGE band patterns were observed in total BM-MNC and CD34 cells in all positive patients suggesting that methylation is a process encompassing both immature and end-stage hematopoietic cells. In a total of 37 patients (14 RA, 3 RAS, 11 RAEB, 4 RAEB-t and 5 with AML secondary to MDS) analyzed, we found promoter hypermethylation of the HIC gene to be significantly increased in advanced MDS (p&lt;0.05). To determine the kinetics of promoter methylation in the single patient, bone marrow from eleven MDS patients, where two or more samples were available, were analyzed (observation time between sampling ranged from 43 to 1132 days, median 284 days). These analyses showed that the patterns of methylation are surprisingly stable over time. When two or more samples were analyzed we found that the number of methylated genes only changed in three of the eleven patients. To delineate the process of hypermethylation we determined the mRNA levels of the DNA methyltransferases (DNMT) 1, 3A, and 3B. Interestingly, all three DNMTs were up-regulated in MDS compared to normal bone marrow (DNMT1 and DNMT3A: p&lt;0.01; DNMT3B: p&lt;0.0001) and DNMT3A and 3B were up-regulated in advanced MDS compared to low-risk MDS (p&lt;0.01). Taken together, these results imply an involvement of promoter hypermethylation in MDS disease progression, and DNMT overexpression as a contributing factor for the aberrant methylation in these patients. Figure: Promoter hypermethylation status over time. A) Development in methylation status in 11 patients. Arrows indicate patients where methylation status changes over time. a) RA, b) RAS, c) RAEB, d) RAEB-t, e) sAML. Black quarters: methylated; white quarters: unmethylated. B) Bisulfite-DGGE experiments for methylation in the p15, HIC , and ER promoters in UPN 2. Figure Figure

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