scholarly journals PATH-29. COMPARATIVE ANALYSIS OF DNA METHYLATION PROFILES ASSOCIATED WITH IDH-WILDTYPE GLIOMA AND GLIONEURONAL TUMOR SUBTYPES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii170-ii170
Author(s):  
Omkar Singh ◽  
Kenneth Aldape
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Sphingolipid Metabolism ◽  
P Value ◽  
Low Grade ◽  
Normal Brain ◽  
Cell Periphery ◽  
Brain White Matter ◽  
Glioneuronal Tumors ◽  
Hypermethylated Genes

Abstract DNA Methylation profiles are highly robust and reproducible as a classification tool. Less is understood regarding the methylation differences that exist among gliomas and glioneuronal tumors. To address this, we analyzed differentially methylated probes (DMPs) of gliomas and glioneuronal tumors compared to normal brain white matter controls. After filtering (Δbeta >0.3, logFC >±1) of significant probes we observed that low grade glioma/glioneuronal tumors (LGGs) had significantly fewer DMPs (Hyper/Hypo) as compared to GBMs. For example, posterior fossa pilocytic astrocytomas (PA’s) showed 2861 DMPs (1916 hypo/945 hyper) versus 9653 for GBM-RTKI ((6563/3090) respectively, while tumors such as PXA and anaplastic PA showed intermediate changes between LGG’s and GBMs. Hypomethylated and hypermethylated probes were analyzed for gene ontology and KEGG pathway enrichment, with LGG subtypes showing hypomethylated probes/genes associated with cell adhesion, blood vessel development and viral infection (P-value = 10-7). In contrast, hypomethylated probes in GBM subtypes were enriched for plasma membrane and cell periphery gene ontologies (P-value = 10-52). With respect to hypermethylated probes, LGG subtypes showed enrichment for myelination, glial cell differentiation and sphingolipid metabolism (P-value = 10-5) while DNA-binding transcription factor activity was seen in GBM subtypes (P-value=10-35). Examples of the most significantly hypermethylated genes in GBM included the transcription factors, GATA3 and PAX9. Intermediate-grade gliomas such as anaplastic PA and PXA showed enrichment of hypermethylated genes similar to GBM, but of lower significance (P-values = 10-6 and 10-4). Overall, understanding of cancer-associated DNA methylation changes in glioma subtypes suggests a hierarchy of biological changes that may underlie the pathogenesis of these tumors and interestingly, highlight tumor types such as PXA and anaplastic PA as having intermediate methylation changes, between benign LGG and GBM. Hypermethylation of transcription-factor genes will be investigated in GBM and compared with changes in gene expression to understand possible roles in the pathogenesis.

High Throughput Methylation Arrays Allow for Identification of Complex Methylation Patterns in MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2437-2437
Author(s):  
Ying Jiang ◽  
Christine L. OKeefe ◽  
Andrew Dunbar ◽  
Anjali Advani ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
High Throughput ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Epigenetic Silencing ◽  
Low Grade ◽  
High Grade ◽  
Methylation Patterns ◽  
Hypermethylated Genes

Abstract Genomic imprinting and epigenetic silencing determine tissue-specific methylation patterns. Altered methylation of CpG islands within gene promoters has been hypothesized as one pathogenetic mechanism operative in myelodysplastic syndrome (MDS). Promoter hypermethylation of various empirically selected tumor suppressor genes has been found in MDS prompting application of hypomethylating drugs in this disease. Identification of hypermethylated genes predicting response to these drugs would have a major impact on clinical practice. However, to date methylation-based prognostic algorithms have not been established. Global analysis of DNA methylation patterns may help to identify hypermethylated genes/promoters associated with the pathogenesis of MDS. Recently, microarray-based DNA methylation analysis platforms enabled a powerful, high-throughput analysis of the methylation status of hundreds of genes. The GoldenGate Methylation Cancer Panel I, spanning 1,536 independent CpG sites selected from 807 selected genes was applied to determine the methylation status in MDS patients (N=51; 21 low grade (RA, MDS-U, RARS or RCMD), 26 high grade (AML or RAEB) and 4 CMML). The methylation status was determined based on an internal reference and compared to healthy controls (N=22). Methylation values were averaged among the patients or analyzed separately for each patient in comparison to average values obtained in controls. Overall, controls showed a lesser degree of methylation than advanced MDS patients (average intensity 0.326 vs. 0.339, p<0.05). Subsequently, we concentrated on hypermethylated genes. There were no genes uniformly hypermethylated in all patients. For 70%, 50%, and 30% of patients with advanced MDS, 1, 26, and 85 loci were concordantly hypermethylated, while in 70%, 50% and 30% of low risk patients 5, 23 and 31 were hypermethylated, respectively. The most consistently hypermethylated genes (>50% of patients), included tumor suppressor genes (DCC, SLC22A18, FAT, TUSC3), genes involved in DNA repair (OGG1, DDB2, BCR, PARP1), cell cycle control (DBC1, SMARCB1), differentiation (MYOD1, TDGF1, FGF2, NOTCH4) and apoptosis (HDAC1, ALOX12, AXIN1). Despite the variability, the aberrant methylation spectrum in CMML, low grade MDS and high grade MDS showed significant overlap (for example FZD9, IL16, EVI2A, MBD2 and BCR), which suggests that these genes may relate to the common tumorigenesis in MDS. Certain genes show specific methylation correlating to the morphologic diagnosis and may serve as diagnostic markers. For example, the promoter of HDAC1 is hypomethylated in 81% of sAML/RAEB1/2 patients but hypermethylated in 81% of low risk cases. To assess the link between epigenetic changes and chromosomal abnormalities, we also investigated methylation pattern of MDS with del5q for selected genes at the 5q locus. Some genes that are involved in apoptosis (WNT1, TNF receptor) and proliferation (MAP3K8, CSF3) were found to be hypermethylated in comparison to controls, suggesting that epigenetic silencing may enhance the effect of haploinsuffciency for some of the genes. In sum, our study, the first application of a high-throughput microarray methylation assay in MDS, demonstrates that complex methylation patterns exist in MDS and may allow for identification for clinically relevant methylation markers.

scholarly journals Comparative Evaluation of SOX2 and p16 Expression in Intraepithelial Neoplasia and Invasive Cancer of Cervix

2021 ◽  
Author(s):  
Sowmya Dayalan ◽  
Vijayashree Raghavan
Keyword(s):  
Transcription Factor ◽  
Invasive Cancer ◽  
P Value ◽  
Low Grade ◽  
High Grade ◽  
Diagnostic Biomarker ◽  
Squamous Intraepithelial Lesion ◽  
Chi Square ◽  
Intraepithelial Lesion ◽  
P16 Expression

Introduction: SRY (Sex determining region Y)-Box Transcription Factor 2 (SOX2), a transcription factor functioning as a stem cell marker has been studied in many cancers for its role as an oncogene. This study evaluates the expression of SOX2 and protein 16 (p16) expression in cervical with the intent to establish their role as a diagnostic biomarker. Aim: To evaluate the nature of SOX2 expression in cervical cancer and in intraepithelial lesions of cervix and compare it with the expression of p16 with the intent to establish its role as a diagnostic biomarker. Materials and Methods: This study was a retrospective observational study conducted in the Department of Pathology, Chettinad Hospital and Research Institute, Chennai, Tamil Nadu, India from October 2018 to September 2019. Archival blocks for study were collected from cases between January 2012 to December 2017. Immunohistochemistry for SOX2 and p16 on 61 cases of cervical lesions including SCC, Low-grade Squamous Intraepithelial Lesion (LSIL), High-grade Squamous Intraepithelial Lesion (HSIL) and normal cervix were done. A chi-square analysis was used to determine the relationship of SOX2 and p16 expression in different lesions and compared the same. All collected data was tabulated and analysed by Statistical Package for Social Sciences (SPSS) version 23.0 and was compared by chi-square tests. Results: In the total 61 cases (majority with LSIL, n=21, 34.43%, SCC were 19 (31.15%), HSIL were 20 (32.79%) and adenosquamous carcinoma were 1 (1.64%), SOX2 (p-value <0.001) and p16 (p-value 0.0016) showed over-expression in SCC and HSIL with significant p-value, LSIL showed low expression. SOX2 and p16 expression was limited to the basal one-third in LSIL cases, whereas it was expressed up to two-third or full thickness in HSIL cases. Also, SOX2 and p16 had a significant relationship with p-value=0.001. SOX2 was sensitive for SCC with 84.21% sensitivity and p16 was sensitive for HSIL with 90% sensitivity. Conclusion: Both SOX2 and p16 show increasing expression as the lesion progresses from low grade dysplasia to high grade dysplasia and invasive cancer and can complement each other to make a definitive diagnosis.

Epigenetic Determinants of Pathogenesis and Resistance to Proteosome Inhibition in Mantle Cell Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3373-3373 ◽  
Author(s):  
Tobias Gellen ◽  
Pei-Yu Kuo ◽  
Rita Shaknovich ◽  
Maria E Figueroa ◽  
Ari Melnick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Tumor Suppressor ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Tumor Suppressor Genes ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Hypermethylated Genes

Abstract Mantle Cell Lymphoma (MCL) is an aggressive tumor accounting for 5% of non Hodgkin’s lymphomas(NHL). Given the poor clinical outcomes in this disease with current therapy, it is of great importance to better understand disease pathogenesis. Since aberrant epigenetic gene regulation is a hallmark of cancer, we hypothesized that an unbiased genome-wide DNA methylation study would identify genes involved in MCL pathogenesis. Moreover, we hypothesized that aberrantly silenced/hypermethylated genes responsible for drug sensitivity in MCL could be pharmacologically manipulated for maximizing clinical benefit. To address these questions, we examined the abundance of DNA methylation in 25,000 promoter fragments using the HELP (HPA II Enzyme Ligation mediated PCR amplification) assay in MCL cell lines. This study revealed s substantial heterogeneity in genomic methylation between cell lines, possibly reflective of underlying biologic diversity in this disease. However, MCL cell lines did display consistent aberrant methylation when compared to naïve B cells extracted from normal human tonsils. Remarkably, among the 102 genes with a methylation fold change in >3 and p<0.0001 the majority (100) were hypermethylated in MCL vs. normal B cells. Amongst these genes we identified five tumor suppressor genes implicated in the pathogenesis of other cancers: Protocadherin 8,Paternally expressed gene 3 (PEG3),Myeloid leukemia factor 1, Transcription Factor AP-2 gamma and Homeobox D8. Interestingly. PEG3 and Protocadherin 8 are both known to be silenced by hypermethylation at their gene promoters in gastric and breast cancer respectively. These genes may also possibly function as tumor suppressor genes in MCL pathogenesis and are excellent candidates for future functional studies. We then integrated methylation and gene expression data to identify loci that were both significantly methylated and suppressed in MCL. To identify the pathways and biological processes most relevant to our data set of methylated genes, we queried the Ingenuity Pathway Analysis (IPA) Knowledge base with the top 560 hypermethylated genes (>2 Standard Deviation) across all MCL cell lines. An unsupervised core analysis from the IPA knowledge base using our gene set revealed gene networks revolving around tumor suppressor TP53 and the NPM1 transcription factor in MCL cell lines. Locus specific confirmation by MassArray confirmed methylation of the distal portion of the TP53 promotor in the MCL cell lines. Recently, the proteosome inhibitor Bortezomib(BZM) has been shown to have specific activity in MCL, with single agent response rates ~40% in heavily pretreated patients. We wondered whether aberrant epigenetic programming might contribute to resistance to this agent and whether reversal of DNA methylation could overcome cellular mechanisms of resistance to Bortezomib. Therefore, to determine whether pharmacologic re-expression of genes could overcome bortezomib resistance, we treated MINO (a Bortezomib-refractory MCL cell line) with two low doses of Decitabine (0.1 uM and 1 uM) for 48 hours and sequentially with 15 nM of Bortezomib (IC50) for an additional 48 hours. Pretreatment of BZM-resistant MINO cells with Decitabine significantly (p<0.001) reduced cell viability as compared to control, suggesting that Decitabine can overcome BZM resistance in this refractory cell line. We are currently determining which genes contribute to this effect and validating these results in patient samples from a prospective trial of BZM+EPOCH. We predict that this will provide the basis for future trials individualizing BZM based therapy based on methylation and gene expression signatures in MCL.

EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

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

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

scholarly journals BIOM-62 SENSITIVE DETECTION AND DISCRIMINATION OF INTRACRANIAL TUMORS BY BLOOD

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii15-ii15
Author(s):  
Farshad Nassiri ◽  
Ankur Chakravarthy ◽  
Shengrui Feng ◽  
Roxana Shen ◽  
Romina Nejad ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Tumors ◽  
Model Performance ◽  
High Sensitivity ◽  
Circulating Tumor Dna ◽  
Low Grade ◽  
Learning Approaches ◽  
Intracranial Tumors ◽  
Cell Of Origin ◽  
Tumor Dna

Abstract BACKGROUND The diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Non-invasive diagnostic approaches, particularly for patients with brain tumours, provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. We reasoned that DNA methylation profiles of circulating tumor DNA in blood can be used as a clinically useful biomarker for patients with brain tumors, given the specificity of DNA methylation profiles for cell-of-origin. METHODS We generated methylation profiles on the plasma of 608 patients with cancer (219 intracranial, 388 extracranial) and 60 healthy controls using a cell-free methylated DNA immunoprecipitation combined with deep sequencing (cfMeDIP-seq) approach. Using machine-learning approaches we generated and evaluated models to distinguish brain tumors from extracranial cancers that may metastasize to the brain, as well as additional models to discriminate common brain tumors included in the differential diagnosis of solitary extra-axial and intra-axial tumors. RESULTS We observed high sensitivity and discriminative capacity for our models to distinguish gliomas from other cancerous and healthy patients (AUC=0.99, 95%CI 0.96–1), with similar performance in IDH mutant and wildtype gliomas as well as in lower- and high-grade gliomas. Excluding non-malignant contributors to plasma methylation did not change model performance (AUC=0.982, 95%CI 0.93–1). Models generated to discriminate intracranial tumors from each other also demonstrated high accuracy for common extra-axial tumors (AUCmeningioma=0.89, 95%CI 0.80–0.97; AUChemangiopericytoma=0.95, 95%CI 0.73–1) as well as intra-axial tumors ranging from low-grade indolent glial-neuronal tumors (AUC 0.93, 95%CI 0.80 – 1) to diffuse intra-axial gliomas with distinct molecular composition (AUCIDH-mutant glioma = 0.82, 95%CI 0.66 -0.98; AUCIDH-wildtype-glioma = 0.71, 95%CI 0.53 – 0.9). Plasma cfMeDIP-seq signals originated from corresponding tumor tissue DNA methylation signals (r=0.37, p&lt; 2.2e-16). CONCLUSIONS These results demonstrate the potential for cfMeDIP-seq profiles to not only detect circulating tumor DNA, but to accurately discriminate common intracranial tumors that share cell-of-origin lineages.

scholarly journals A urine-based DNA methylation assay to facilitate early detection and risk stratification of bladder cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Weimei Ruan ◽  
Xu Chen ◽  
Ming Huang ◽  
Hong Wang ◽  
Jiaxin Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bladder Cancer ◽  
Risk Stratification ◽  
Early Stage ◽  
Operative Risk ◽  
Low Grade ◽  
Single Center ◽  
Detection Model ◽  
Methylation Assay ◽  
Muscle Invasive

Abstract Background Current non-invasive tests have limited sensitivities and lack capabilities of pre-operative risk stratification for bladder cancer (BC) diagnosis. We aimed to develop and validate a urine-based DNA methylation assay as a clinically feasible test for improving BC detection and enabling pre-operative risk stratifications. Methods A urine-based DNA methylation assay was developed and validated by retrospective single-center studies in patients of suspected BC in Cohort 1 (n = 192) and Cohort 2 (n = 98), respectively. In addition, a prospective single-center study in hematuria patient group (Cohort 3, n = 174) was used as a second validation of the model. Results The assay with a dual-marker detection model showed 88.1% and 91.2% sensitivities, 89.7% and 85.7% specificities in validation Cohort 2 (patients of suspected BC) and Cohort 3 (patients of hematuria), respectively. Furthermore, this assay showed improved sensitivities over cytology and FISH on detecting low-grade tumor (66.7–77.8% vs. 0.0–22.2%, 0.0–22.2%), Ta tumor (83.3% vs. 22.2–41.2%, 44.4–52.9%) and non-muscle invasive BC (NMIBC) (80.0–89.7% vs. 51.5–52.0%, 59.4–72.0%) in both cohorts. The assay also had higher accuracies (88.9–95.8%) in diagnosing cases with concurrent genitourinary disorders as compared to cytology (55.6–70.8%) and FISH (72.2–77.8%). Meanwhile, the assay with a five-marker stratification model identified high-risk NMIBC and muscle invasive BC with 90.5% sensitivity and 86.8% specificity in Cohort 2. Conclusions The urine-based DNA methylation assay represents a highly sensitive and specific approach for BC early-stage detection and risk stratification. It has a potential to be used as a routine test to improve diagnosis and prognosis of BC in clinic.

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.

scholarly journals BMI trajectory in childhood is associated with asthma incidence at young adulthood mediated by DNA methylation

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Rutu Rathod ◽  
Hongmei Zhang ◽  
Wilfried Karmaus ◽  
Susan Ewart ◽  
Latha Kadalayil ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Young Adulthood ◽  
R Package ◽  
P Value ◽  
Mediation Effects ◽  
Asthma Incidence ◽  
Path Analyses ◽  
Children And Parents ◽  
Bmi Trajectories ◽  
Bmi Trajectory

Abstract Purpose Body mass index (BMI) is associated with asthma but associations of BMI temporal patterns with asthma incidence are unclear. Previous studies suggest that DNA methylation (DNAm) is associated with asthma status and variation in DNAm is a consequence of BMI changes. This study assessed the direct and indirect (via DNAm) effects of BMI trajectories in childhood on asthma incidence at young adulthood. Methods Data from the Isle of Wight (IoW) birth cohort were included in the analyses. Group-based trajectory modelling was applied to infer latent BMI trajectories from ages 1 to 10 years. An R package, ttscreening, was applied to identify differentially methylated CpGs at age 10 years associated with BMI trajectories, stratified for sex. Logistic regressions were used to further exclude CpGs with DNAm at age 10 years not associated with asthma incidence at 18 years. CpGs discovered via path analyses that mediated the association of BMI trajectories with asthma incidence in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Children and Parents (ALSPAC). Results Two BMI trajectories (high vs. normal) were identified. Of the 442,474 CpG sites, DNAm at 159 CpGs in males and 212 in females were potentially associated with BMI trajectories. Assessment of their association with asthma incidence identified 9 CpGs in males and 6 CpGs in females. DNAm at 4 of these 15 CpGs showed statistically significant mediation effects (p-value < 0.05). At two of the 4 CpGs (cg23632109 and cg10817500), DNAm completely mediated the association (i.e., only statistically significant indirect effects were identified). In the ALSPAC cohort, at all four CpGs, the same direction of mediating effects were observed as those found in the IoW cohort, although statistically insignificant. Conclusion The association of BMI trajectory in childhood with asthma incidence at young adulthood is possibly mediated by DNAm.

Transcription factor 3 controls cell proliferation and migration in glioblastoma multiforme cell lines

2016 ◽  
Vol 94 (3) ◽  
pp. 247-255 ◽  
Author(s):  
Ruiting Li ◽  
Yinghui Li ◽  
Xin Hu ◽  
Haiwei Lian ◽  
Lei Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glioblastoma Multiforme ◽  
Cell Lines ◽  
Normal Brain ◽  
Phosphatidylinositol 3 Kinase ◽  
T Cell Factor ◽  
And Migration ◽  
Induced Apoptosis ◽  
Proliferation And Migration ◽  
Transcription Factor 3

Transcription factor 3 (TCF3) is a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family. Recent studies have demonstrated its potential carcinogenic properties. Here we show that TCF3 was upregulated in glioma tissues compared with normal brain tissues. This upregulation of the TCF3 gene probably has functional significance in brain-tumor progression. Our studies on glioblastoma multiforme (GBM) cell lines show that knock-down of TCF3 induced apoptosis and inhibited cell migration. Further analysis revealed that down-regulation of TCF3 gene expression inhibits Akt and Erk1/2 activation, suggesting that the carcinogenic properties of TCF3 in GBM are partially mediated by the phosphatidylinositol 3-kinase–Akt and MAPK–Erk signaling pathways. Considered together, the results of this study demonstrate that high levels of TCF3 in gliomas potentially promote glioma development through the Akt and Erk pathways.

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