scholarly journals DNA Methylation of Endoglin Pathway Genes in Pregnant Women With and Without Preeclampsia

2020 ◽  
Vol 13 ◽  
pp. 251686572095968
Author(s):  
Allison H Rietze ◽  
Yvette P Conley ◽  
Dianxu Ren ◽  
Cindy M Anderson ◽  
James M Roberts ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Control Participant ◽  
Sample Collection ◽  
Promoter Regions ◽  
Participant Group

Objective: We compared blood-based DNA methylation levels of endoglin ( ENG) and transforming growth factor beta receptor 2 ( TGFβR2) gene promoter regions between women with clinically-overt preeclampsia and women with uncomplicated, normotensive pregnancies. Methods: We used EpiTect Methyl II PCR Assays to evaluate DNA methylation of CpG islands located in promoter regions of ENG (CpG Island 114642) and TGFβR2 (CpG Island 110111). Preeclampsia was diagnosed based on blood pressure, protein, and uric acid criteria. N = 21 nulliparous preeclampsia case participants were 1:1 frequency matched to N = 21 nulliparous normotensive control participants on gestational age at sample collection (±2 weeks), smoking status, and labor status at sample collection. Methylation values were compared between case and control participant groups [( ENG subset: n = 20 (9 cases, 11 controls); TGFβR2 subset: n = 28 (15 cases, 13 controls)]. Results: The majority of the preeclampsia cases delivered at ⩾34 weeks’ gestation (83%). Average methylation levels for ENG ([M ± (SD)]; Case Participant Group = 6.54% ± 4.57 versus Control Participant group = 4.81% ± 5.08; P = .102) and TGFβR2 (Case Participant Group = 1.50% ± 1.37 vs Control Participant Group = 1.70% ± 1.40; P = .695) promoter CpG islands did not differ significantly between the participant groups. Removal of 2 extreme outliers in the ENG analytic subset revealed a trend between levels of ENG methylation and pregnancy outcome (Case Participant Group = 5.17% ± 2.16 vs Control Participant Group = 3.36% ± 1.73; P = .062). Conclusion: Additional epigenetic studies that include larger sample sizes, investigate preeclampsia subtypes, and capture methylation status of CpG island shores and shelves are needed to further inform us of the potential role that ENG and TGFβR2 DNA methylation plays in preeclampsia pathophysiology.

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.

Genome-Wide DNA Methylation Profile of CLL with 17p del Allowed Identification of Multiple Epigenetically Inactivated Molecular Pathways with Prognostic Value in Human Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 492-492
Author(s):  
Wei-Gang Tong ◽  
William G. Wierda ◽  
Neby Bekele ◽  
Shao-Qing Kuang ◽  
Michael J. Keating ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Cpg Island ◽  
Trichostatin A ◽  
Methylation Status ◽  
Cpg Islands ◽  
Human Leukemia ◽  
Dna Hypomethylation ◽  
Line P ◽  
Normal Controls

Abstract Aberrant DNA methylation of multiple promoter associated CpG islands is a very prevalent phenomenon in human leukemias. Data from our laboratory indicates that methylation profiling allows the identification of leukemia patients with different risk and prognosis. Despite the advances in the understanding of the molecular biology of CLL, few studies of DNA methylation have been performed in CLL. In the current study, we have developed a new assay combining MCA (Methylated CpG island Amplification) with the Agilent promoter CpG array to identify simultaneously hundreds of abnormally methylated CpG islands in CLL. To perform this, we compared DNA from two CLL patients with 17p del (tester) with that of CD19+ B cells from two age-matched controls (driver). We identified 280 promoter CpG islands differentially methylated in CLL compared to normal controls. Most of these genes are located on chromosomes 19 (16%), 16 (11%), 17 (10%) and 11 (9%). We also performed interaction pathway and functional analysis of these 280 genes using the online Ingenuity Pathway Analysis tools. The initial analysis divided these genes into 25 functional networks, with the majority of genes fall into top 10 networks. The major functions of genes in these interaction networks involve cancer, organ development, cell death, drug metabolism, DNA replication and repair. We validated 22 of these genes (ADCY5, R-spondin1, LHX1, GALGT2, TFAP2C, ING1, SOX11, SOX14, SALL1, LTBP2, APP, DXL1, DLX4, KLK10, BCL11B, NR2F2, FAM62T, HAND2, BNC1, SPOCK, Prima1 and MLL1) in samples from 78 CLL patients and 10 age-matched normal controls. The characteristics of the 78 patients are: median age 59 (range 39–79), male 70%, Rai stage 0–II/III–IV (83%/17%), IgVH unmutated 49%, ZAP-70 positive 33%. Our results indicate that most of the genes identified by the array are frequently hypermethylated in CLL patients compared with healthy controls. Methylation frequency ranged from 20%–100% in CLL patients. Expression analysis of four selected genes (LHX1, GALGT2, TFAP2C and Prima1) in human leukemia cell lines and CLL patient samples by real-time PCR further confirmed methylation associated gene silencing, and treatment of these cell lines with hypomethylating agent 5-aza-2′-deoxycitidine with or without the HDAC inhibitor Trichostatin A resulted in gene re-expression and induction of DNA hypomethylation. We also analyzed the association of methylation status of these genes with IgVH mutation status, ZAP70 expression and patient survival. Unmutated IgVH was associated with increased methylation levels of LINE (p<0.0001), which is a marker for global gene methylation and SALL1 (p=0.00008). Expression of ZAP-70 (>20%) was associated with increased methylation levels of LINE (p<0.00001), MLL (p=0.02) and SALL1 (p=0.048). Further analysis showed that methylation status of LINE (p=0.007), SALL1 (p=0.019), ADCY5 (p=0.021), R-spondin1 (p=0.002) and APP (p=0.002) correlated with survival. In conclusion, our studies indicate that MCA/promoter array technique allows the identification of large number of promoter CpG islands aberrantly methylated in CLL and also the identification of novel tumor suppressors and signaling pathways that could be important in the tumorigenesis of CLL and other hematological malignancies.

Genome-Wide Epigenetic Analysis of Cancer Stem Cells (CSCs) In Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3640-3640 ◽  
Author(s):  
Jumpei Yamazaki ◽  
Marcos R Estecio ◽  
Jaroslav Jelinek ◽  
David Graber ◽  
Yue Lu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Cell Population ◽  
Progenitor Cell ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Significant Difference

Abstract Abstract 3640 Background & Aims: The hypothesis that cancer is driven by Cancer Stem Cells (CSCs or Cancer-Initiating Cell) has recently attracted a great deal of attention. Epigenetic mechanism such as DNA methylation and histone modification play an important role in cancer cells and also in normal stem cells. However, their role remains unclear in CSCs. We sought to determine if CSCs have distinct epigenetic patterns in acute myeloid leukemia (AML). Methods: Peripheral blood samples in AML patients were separated to obtain stem cells (CD34+CD38-) and progenitor cells (CD34+CD38+) by magnetic cell sorting (MACS®, Myltenyi biotec). To study DNA methylation in CSCs in AML, we performed genome wide screening using methylated CpG island microarray (MCAM), which detects 7202 promoter CpG islands, 1348 non-promoter CpG islands, and 632 non-CpG island promoter methylation. MCAM was performed on 4 AML patient samples Next, we evaluated the methylation status of 7 genes which showed apparent higher DNA methylation in stem cells or progenitor cells in MCAM analysis, using a quantitative bisulfite-pyrosequencing for each population of stem cell, progenitor cell, and mature cells (CD34-) from peripheral blood samples in 6 AML patients. For histone modification analysis, we used Chromation immuprecipitation followed by massively parallel sequencing (ChIP-Seq) for stem cell and progenitor cell populations for H3K4me3 which is known to be a marker for activated genes. Results: By MCAM, we found minimal differences between stem cells and progenitor cells present in 2 out of 4 AML patients. Those few genes (<1%) which were shown to have higher DNA methylation in stem or progenitor cells by MCAM analysis were likely false positives, as no significant difference was found when analyzed by quantitative bisulfite-pyrosequencing. DNA methylation status for stem cell-related gene (OCT4, SOX2, MYC, HOXB4, and KLF4) also showed no significant difference. By ChIP-seq analysis, we found differences in 2362 genes between stem cells and progenitor cells. In stem cells, H3K4me3 was enriched in genes (Bmi1, Notch1, Wnt1, and etc) which are known to be important for stem cell function, but they were not enriched in the progenitor cell population. In pathway analysis of the H3K4me3 data, Hypoxia-Inducible Factor signaling, NFkB signaling, and p53 signaling are found to be enriched specifically in the stem cell population whereas Cellular Growth and Cell Cycle, and DNA Damage Response signaling are found in the progenitor cell population. Conclusions: There is no significant difference in DNA methylation between stem cell, progenitor cell or mature cell populations in AML. DNA methylation of promoter CpG islands is unlikely to explain tumor hierarchy in AML. Rather, histone modifications seem to have a greater significance in this regard. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1366-1373 ◽  
Author(s):  
Heike Kroeger ◽  
Jaroslav Jelinek ◽  
Marcos R. H. Estécio ◽  
Rong He ◽  
Kimie Kondo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Leukemia Cell ◽  
Transcription Start Sites ◽  
Remission Maintenance ◽  
Acute Myeloid

AbstractDNA methylation of CpG islands around gene transcription start sites results in gene silencing and plays a role in leukemia pathophysiology. Its impact in leukemia progression is not fully understood. We performed genomewide screening for methylated CpG islands and identified 8 genes frequently methylated in leukemia cell lines and in patients with acute myeloid leukemia (AML): NOR1, CDH13, p15, NPM2, OLIG2, PGR, HIN1, and SLC26A4. We assessed the methylation status of these genes and of the repetitive element LINE-1 in 30 patients with AML, both at diagnosis and relapse. Abnormal methylation was found in 23% to 83% of patients at diagnosis and in 47% to 93% at relapse, with CDH13 being the most frequently methylated. We observed concordance in methylation of several genes, confirming the presence of a hypermethylator pathway in AML. DNA methylation levels increased at relapse in 25 of 30 (83%) patients with AML. These changes represent much larger epigenetic dysregulation, since methylation microarray analysis of 9008 autosomal genes in 4 patients showed hypermethylation ranging from 5.9% to 13.6% (median 8.3%) genes at diagnosis and 8.0% to 15.2% (median 10.6%) genes in relapse (P < .001). Our data suggest that DNA methylation is involved in AML progression and provide a rationale for the use of epigenetic agents in remission maintenance.

Identification of 41 Novel Promoter-Associated CpG Islands Methylated in Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1126-1126 ◽  
Author(s):  
Jaroslav Jelinek ◽  
Rajan Mannari ◽  
Jean-Pierre Issa
Keyword(s):  
Gene Silencing ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Response To Treatment ◽  
Published Data ◽  
Promoter Regions ◽  
Cpg Dinucleotides ◽  
A Genome ◽  
Methylation Profiling

Abstract DNA methylation within promoter-associated CpG islands is a well-recognized mechanism of gene silencing and plays an important role in the development of malignancies. CpG dinucleotides in human DNA are methylated at 5′-cytosine with the exception of areas with dense concentration of CpGs (CpG islands) located in gene promoter regions. In cancer cells, methylation of CpG islands in promoter regions of tumor suppressor genes is a frequent epigenetic change with a gene-silencing effect analogous to inactivating mutations. Methylation profiling can identify biologically and clinically distinct tumor subgroups by mapping the methylation status of multiple genes, and reports in AML and ALL suggest associations between methylation and poor prognosis. Identification of methylated CpG islands can shed new light on the biology of leukemia. We used Methylated CpG Island Amplification coupled with Representative Difference Analysis (MCA-RDA) as a genome-wide screen for promoter-associated CpG islands methylated in leukemic and/or myeloproliferative cell lines and primary malignant cells, but unmethylated in blood cells from normal controls. We identified 51 unique promoter-associated CpG islands in 321 sequenced clones recovered by MCA-RDA. Forty-one CpG islands belonged to known genes, and 10 to annotated mRNAs. Of the genes with known function, 8 are involved in signaling, 7 in transcription, 3 in dephosphorylation, 2 in oxido-reductive processes, 2 in NO synthesis, 2 in adhesion, 2 in solute transport, and 2 in DNA replication. Seven out of the 51 genes were previously reported as methylated in cancer or leukemia (CDH13, HLA-B, HLA-C, PGR, SCGB3A1, SLC26A4, TERT), thus validating the MCA-RDA approach. Of the 41 new hypermethylated CpG islands recovered, 20 corresponded to genes of known function. Published data infer an association with cancer for 10 of these genes (CTDSPL, ECGF1, EDG4, FOXD2, NOR1, NOS3, OLIG2, SLC16A1, TLE1, WNT5B), and no reports were found for the other 10 genes (CNR1, FADS, FBXW3, FGD1, NPM2, P518, PDE4DIP, SNCB, TCEA3, VENTX2). To further validate our findings we are assessing the methylation status of these genes by bisulfite pyrosequencing. Analyses of the bone marrow samples from AML, ALL, CML and MDS patients are ongoing. Our preliminary data confirm methylation of H-cadherin precursor (CDH13), progesterone receptor (PGR) in AML and ALL and cannabinoid receptor 1 (CNR1) in ALL (Table). In conclusion, MCA-RDA identified methylation of 41 new and 10 previously reported promoter-associated CpG islands in leukemia. Functional studies of these may shed new light on the biology of leukemias, and these genes may be useful for methylation profiling of leukemias for prognosis and response to treatment. Promoter CpG Island Methylation Gene AML ALL Methylation levels over 10% for CDH13 and PGR and over 25% for CNR1 were scored as positive. CDH13 5/23 22% 12/19 63% PGR A Isoform 11/22 50% 12/18 67% PGR B Isoform 17/24 71% 5/13 38% CNR1 0/24 0% 3/18 17%

Genome Wide Study of DNA Methylation In AML

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3618-3618
Author(s):  
Marwa Saied ◽  
Sabah Khaled ◽  
Thomas Down ◽  
Jacek Marzec ◽  
Paul Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cpg Island ◽  
Cpg Islands ◽  
Differential Methylation ◽  
Methylation Analysis ◽  
Promoter Regions ◽  
Gene Body Methylation ◽  
Normal Bone ◽  
Genome Wide

Abstract Abstract 3618 DNA methylation is the most stable epigenetic modification and has a major role in cancer initiation and progression. The two main aims for this research were, firstly, to use the genome wide analysis of DNA methylation to better understand the development of acute myeloid leukemia (AML). The second aim was to detect differentially methylated genes/regions between certain subtypes of AML and normal bone marrow (NBM). We used the methylated DNA immunoprecipitation technique followed by high-throughput sequencing by Illumina Genome Analyser II (MeDIP -seq) for 9 AML samples for which ethical approval has been obtained. The selected leukemias included three with the t(8; 21), three with the t(15; 17) translocations and three with normal karyotypes (NK). The control samples were 3 normal bone marrows (NBMs) from healthy donors. The number of reads generated from Illumina ranged between 18– 20 million paired-end reads/lane with a good base quality from both ends (base quality > 30 represented 75%-85% of reads). The reads were aligned using 2 algorithms (Maq and Bowtie) and the methylation analysis was performed by Batman software (Bayesian Tool for Methylation Analysis). The creation of this genome-wide methylation map for AML permits the examination of the patterns for key genetic elements. Investigation of the 35,072 promoter regions identified 80 genes, which showed a significant differential methylation levels in leukemic cases in comparison to NBM; consistently high methylation levels in leukaemia were detected in the promoters of 70 genes e.g. DPP6, ID4, DCC, whereas high methylation levels in NBM, lost in leukaemia was observed in 10 genes e.g. ATF4. For each AML subtype, we also identified significant differentially methylated promoter regions e.g. PAX1 for t(8; 21), GRM7 for t(15; 17), NPM2 for NK. An analysis of gene body methylation identified 49 genes with significantly higher methylation in AML in comparison to NBM e.g. MYOD1 and 31 genes with a higher methylation in NBMs than AML e.g. GNG8. A similar analysis of 23,600 CpG islands identified 400 CpG islands with significant differential methylation levels between leukaemia and NBMs (212 CpG islands were found to have significantly increased methylation in leukaemia and 188 CpG islands had significantly higher methylation in NBMs). The pattern of methylation in CpG island “shores” (2 KB from either side of each CpG island) has been investigated and 312 CpG island shores showed a higher methylation in leukaemia and 88 CpG shores had a significant increase methylation levels in NBMs. This genome wide methylation map has been validated by using direct bisulfite sequencing of the regions identified above (Spearman r= 0.8, P <0.0001) and also by using Illumina Infinium assay (Spearman r= 0.7 P <0.0001) which interrogates regions at single representative CpGs. Comparison of previous array based gene expression data with this methylation map revealed a significant negative correlation between promoter methylation and gene expression (Pearson r= -0.9, P< 0.0001) while, gene body methylation showed a small negative correlation with gene expression, that was found in genes of CpG density >3% (Pearson r= -0.3, P< 0.0001). Conclusion: we have established a high-resolution (100bp) map of DNA methylation in AML and thus identified a novel list of genes, which have significantly differential methylation levels in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Decoupling of DNA Methylation Status and Gene Expression Levels in Aging Individuals

2018 ◽  
Vol 4 (2) ◽  
pp. 100040 ◽  
Author(s):  
Anna Wierczeiko ◽  
David Fournier ◽  
Hristo Todorov ◽  
Susanne Klingenberg ◽  
Kristina Endres ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Methylation Status ◽  
Cpg Islands ◽  
Age Groups ◽  
Epigenetic Factors ◽  
Promoter Regions ◽  
Methylation Patterns ◽  
The Impact ◽  
Gene Expression Levels

Aging is a multi-factorial process, where epigenetic factors play one of the major roles in declines of gene expression and organic function. DNA methylation at CpG islands of promoters can directly change the expression of the neighbouring gene mostly through inhibition. Furthermore, it is known that DNA methylation patterns change during aging In our study, we investigated gene regulation through DNA methylation of genes up- and downregulated in long-lived people compared to a younger cohort. Our data revealed that comparatively highly methylated genes were associated with high expression in long-lived people (e.g. over 85). Genes with lower levels of methylation were associated with low expression. These findings might contradict the general model used to associate methylation status with expression. Indeed, we found that methylation in the promoter regions of all investigated genes is rather constant across different age groups, meaning that the disparity between methylation and expression only happens in older people. A potential explanation could be the impact of other epigenetic mechanisms, possibly related to stress.

scholarly journals DNA Methylation of Human Choline Kinase Alpha Promoter-Associated CpG Islands in MCF-7 Cells

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 853
Author(s):  
Siti Aisyah Faten Mohamed Sa’dom ◽  
Sweta Raikundalia ◽  
Shaharum Shamsuddin ◽  
Wei Cun See Too ◽  
Ling Ling Few
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Binding Site ◽  
Promoter Activity ◽  
Cytosine Methylation ◽  
Cpg Island ◽  
Cpg Islands ◽  
Site Directed Mutagenesis ◽  
Choline Kinase ◽  
Mcf 7

Choline kinase (CK) is the enzyme catalyzing the first reaction in CDP-choline pathway for the biosynthesis of phosphatidylcholine. Higher expression of the α isozyme of CK has been implicated in carcinogenesis, and inhibition or downregulation of CKα (CHKA) is a promising anticancer approach. This study aimed to investigate the regulation of CKα expression by DNA methylation of the CpG islands found on the promoter of this gene in MCF-7 cells. Four CpG islands have been predicted in the 2000 bp promoter region of ckα (chka) gene. Six CpG island deletion mutants were constructed using PCR site-directed mutagenesis method and cloned into pGL4.10 vectors for promoter activity assays. Deletion of CpG4C region located between –225 and –56 significantly increased the promoter activity by 4-fold, indicating the presence of important repressive transcription factor binding site. The promoter activity of methylated full-length promoter was significantly lower than the methylated CpG4C deletion mutant by 16-fold. The results show that DNA methylation of CpG4C promotes the binding of the transcription factor that suppresses the promoter activity. Electrophoretic mobility shift assay analysis showed that cytosine methylation at MZF1 binding site in CpG4C increased the binding of putative MZF1 in nuclear extract. In conclusion, the results suggest that DNA methylation decreased the promoter activity by promoting the binding of putative MZF1 transcription factor at CpG4C region of the ckα gene promoter.

Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex

1990 ◽  
Vol 10 (4) ◽  
pp. 1492-1497
Author(s):  
S J Kim ◽  
P Angel ◽  
R Lafyatis ◽  
K Hattori ◽  
K Y Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Normal Development ◽  
Control Function ◽  
Transcriptional Start Site ◽  
Expression Vectors ◽  
Tgf Beta ◽  
Promoter Regions ◽  
Growth Factor Beta

The multifunctional actions of transforming growth factor beta 1 (TGF-beta 1) indicate that it has a pivotal control function in many physiological and pathological processes. An important property of TGF-beta 1 is its ability to activate its own mRNA expression and thereby increase its own secretion. Two distinct regions of the promoter of the TGF-beta 1 gene are responsive to autoregulation: one 5' to the upstream transcriptional start site and another located between the two major start sites. In both promoter regions, autoinduction is mediated by binding of the AP-1 (Jun-Fos) complex. An important contribution to this positive regulation is the autoactivation of c-jun transcription by AP-1. Cotransfection of antisense c-jun or antisense c-fos expression vectors prevents TGF-beta 1 autoinduction. These results demonstrate that both components of the AP-1 complex are required for TGF-beta 1 autoinduction. Induction of jun expression by TGF-beta 1, as well as jun autoinduction, may amplify the action of TGF-beta 1 during normal development and oncogenesis.

scholarly journals CMET-30. COMPREHENSIVE METHYLOME ANALYSIS OF EGFR-MUTANT PRIMARY LUNG ADENOCARCINOMA AND MATCHED BRAIN METASTASIS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi58-vi58
Author(s):  
Yasin Mamatjan ◽  
Michael Cabanero ◽  
Jeffrey Zuccato ◽  
Jessica Weiss ◽  
Shirin Karimi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Metastasis ◽  
Lung Adenocarcinoma ◽  
Immune Cell ◽  
Methylation Status ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Promoter Regions ◽  
Primary Lung Adenocarcinoma ◽  
Egfr Mutant

Abstract Brain metastasis (BM) in patients with EGFR-mutant lung adenocarcinoma is a major determinant of overall survival. Novel insight into the genetic and epigenetic underpinnings of BM development is lacking. The aim of this study is to compare the methylome of EGFR-mutant primary lung adenocarcinoma (EGFRM-PLA) and matched BM to identify important alterations for the mechanisms of BM. Matched EGFRM-PLA and BM tumors from seven patients were profiled using the Illumina Infinium MethylationEPIC BeadChip array. Unsupervised clustering analyses of the 14 samples showed a similar whole DNA methylation signatures between EGFRM-PLA and BM tumors. Furthermore, PCA plot highlighted that seven matched BM and lung tumor samples were clustered together closely based on matching pairs for the most variable probes (2.5K to 10K). These observations indicate high level of concordance and the same cell of origin. However, these fourteen samples clustered into two groups based on tumor site being lung or brain based on 83K differentially methylated CpG sites. Of the 83K probes, 2.4K were either hypermethylated or hypomethylated in all lung samples. A quarter of these 2.4K probes were located in promoter regions. Specifically, we identified differences in methylation status of EGFR/ALK promoter regions in lung tumors versus BM. CNV analyses showed higher deep deletions of chromosomes and genes in BM compared to EGFRM-PLA. Leukocytes unmethylation for purity (LUMP) scores which indicate immune cell infiltration were similar between lung and BM pairs (Mean LUMP_score=0.64) consistent with high immune cell infiltration. Our results indicated a similar whole DNA methylation signature of EGFRM-PLA and matched BM, while comprehensive analysis identified important differentially methylated probes. Distinct differences in CNV alterations were observed in lung versus brain samples. The BM and EGFRM-PLA showed similar tumor purity and immune cell components. Overall, tumor methylation profiling provides clinically important information regarding biology of BM in EGFRM-PLA.

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