The regulation of miRNA expression by DNA methylation in hepatocellular carcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE49554 | GEO | 2015/08/05
SECONDARY ACCESSION(S): PRJNA214358
REPOSITORIES: GEO
Similar Datasets
Project description:Emerging evidences indicate that microRNAs (miRNAs) are often deregulated and have fundamental roles in hepatocellular carcinoma (HCC). However, the mechanism underlying miRNA dysregulation in HCC is still elusive. In this report, we used an integrated analysis strategy combining methylated DNA immunoprecipitation chip (MeDIP-chip) and miRNA expression microarray data to study the correlation between aberrant methylation and dysregulation of miRNA in HCC. In all, we showed that global miRNA methylation profiles were significantly different between cancerous and normal hepatocytes, and abnormal methylation was an important mechanism governing miRNA expression in HCC. MeDIP-chip was processed in cancerous hepatocytes SK-HEP-1, HepG2, MHCC97-H and normal hepatocytes PHHC-4-1, PHHC-4-2, PHHC-4-3 (3 technical repeat of PHHC-4). MiRNA microarray were processed for cancerous hepatocytes SK-HEP-1, HepG2, Hep3B, Huh7, MHCC97-H, MHCC97-L, SMMC-7721 and normal hepatocytes PHHC-1, PHHC-2, PHHC-3. Then an integrated analysis strategy combining MeDIP-chip and miRNA expression microarray [GSE20077] were used to study the correlation of aberrant DNA methylation and dysregulation of miRNAs.
2015-08-05 | E-GEOD-49554 | biostudies-arrayexpress
Project description:<p>Our current understanding of autism spectrum disorders (ASD) delineates a highly heritable, yet etiologically heterogeneous disease. Forward genetic approaches to find disease associated mutations or common variation have been successful and continue to offer considerable power. Yet, given the accumulating evidence for very significant heterogeneity and environmental influences, complementary approaches to classic forward genetics become necessary. Genetic polymorphism and mutation data to date have identified dozens of causal or contributory variants, yet our preliminary data from autism brain suggest that common molecular pathways are involved in a significant subset of cases. This convergence at the tissue level suggests that other mechanisms, specifically epigenetic changes, combined with genetic background, are contributing to such final common pathways. We further tested this hypothesis by taking a comprehensive and integrative genome-wide approach to assessing brain gene-expression, miRNA levels and the related, causal epigenetic mechanisms in ASD etiology. </p> <p>We performed RNA-seq analyses of four cerebral cortical regions and cerebellum from ASD cases and controls, to assess mRNA, miRNA, and splicing isoform regulation. In parallel, we identified key differences in chromatin state and DNA methylation across multiple brain regions in the same ASD and control individuals used in the expression analyses using ChIP-Seq and MeDIP. We assessed the mechanisms by which changes in DNA methylation, histone modification, and DNA sequence contribute to the observed differences in gene expression. This work, which represents an unprecedented effort to unify these often disparate data (usually produced without integration in mind), delineates potential shared molecular pathways in ASD and the underlying mechanism of these differences at the level of miRNA, the chromatin regulatory apparatus, and DNA methylation.</p> <p>The following substudies are part of the PsychENCODE release at dbGaP and offer additional molecular data: <ul> <li>PsychENCODE: RNA-Sequencing - SRRM4 Splicing Study <a href="study.cgi?study_id=phs000872">phs000872</a></li> <li>PsychENCODE: Global Changes in Patterning, Splicing and lncRNAs <a href="study.cgi?study_id=phs001061">phs001061</a></li> <li>PsychENCODE: Chromatin Contact Map in Fetal Cortical Laminae <a href="study.cgi?study_id=phs001190">phs001190</a></li> <li>PsychENCODE: Epigenetic Dysregulation in Autism Spectrum Disorder <a href="study.cgi?study_id=phs001220">phs001220</a></li> </ul> </p>
| phs001022 | dbGaP
Project description:Purpose: MeDIP based Next-generation sequencing (NGS) has revolutionized differential and funtional mapping of genome-wide methylation signature. The goals of this study are to compare MeDIP-seq derived methylome profiling of miRNA in EOC samples and normal ovary tissue samples, and their downstream expression analysis through quantitative reverse transcription polymerase chain reaction (qRT–PCR) methods. Methods: Six EOC tissue and two normal ovary samples were processed and genomic DNA was isolated. MeDIP-seq based library was prepared and for all eight samples and cluster generation and pair end sequencing was performed on Illumina TrueSeq 500 platform. Adptor triming, low quality read and duplicate reads were removed. High qulity read were aligned using BWA-Mem tools. Methylated genome regions and differential methylation analysis was performed using diffReps (v1.55.6). In addition, hypomethylation/hypermethylation of miRNA genes and thier downstream expression analysis was evaluated using qRT–PCR SYBR Green based assays Results: Using an optimized data analysis workflow, we mapped about ~60-80 million sequence reads per sample to the human. arround 2,24,929 DMR (p<0.05) were identified as differentially methylated regions and out of them 45% were hypermethylated and 55% were hypomethylated compared to normal samples. genomic distribution of DMRs revealed higher enrichment in Gene body, and in other intergenic region. Arround 50 proximal promoter regions of miRNA genes were hypomethylated, while 80 were fall in hypermethylated region. Out of these three miRNA from hypomethylated were screened for further qRT-PCR based expression analysis. qRT-PCR expression analysis revealed upregulation of candidate miRNA in EOC compared to normal samples. Upregulated expression profile of three miRNA obtained from qRT-PCR confiremed there association with hypomethylation of miRNA genes and their downstream expression. Conclusions: Our study revealed genome-wide methylome analysis of ovarian cancer tissue samples, using MeDIP NGS based approach. The optimized data analysis workflows reported here should provide a association between gene methylation and their downream expression profiles. Our results show that MeDIP-seq offers a comprehensive and more accurate genome-wide differential methylation analysis of ovarian cancer tissue. We conclude that MeDIP-seq based analysis would help in understanding of differential methylation characteristics of cancerous and non-cancerous ovarian tissue samples and could allow us to understand complex biological functions
2021-10-05 | GSE180292 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE38926: Patterns of aberrant DNA methylation after toxicant-induced malignant transformation (MeDIP-chip dataset 1) GSE38928: Patterns of aberrant DNA methylation after toxicant-induced malignant transformation (MeDIP-chip dataset 2) GSE38929: Patterns of aberrant DNA methylation after toxicant-induced malignant transformation (miRNA dataset) Refer to individual Series
2012-06-25 | E-GEOD-38930 | biostudies-arrayexpress
Project description:MicroRNAs is a rapidly expanding area expected to change the way in which diseases will be diagnosed, treated and monitored in the future. Hepatocellular carcinoma (HCC) shows a rising incidence with high mortality but lack of effective targeted therapies. We identified the aberrantly expressed miRNAs involved in HCC through the comparison of miRNA expression profiling in cancerous hepatocytes with that in normal primary human hepatocytes and found 37 dysregulated miRNAs in HCC. These aberrantly expressed miRNAs may provide insights into pathogenesis of HCC and thus may be used for diagnosis and therapy. Over the past few years, though several studies have uncovered aberrant miRNA expression profiles in HCC compared with matched nonmalignant tissues, the overlap of deregulated miRNAs from different platforms is limited. To solve this problem, we recommend a method that using primary cancer cells or cancer cell lines and nonmalignant primary cells to identify the specific aberrantly miRNA expression profiles in HCC and even in other types of cancer. Here, we identified the aberrantly expressed miRNAs involved in hepatoma through the comparison of miRNA expression profiling in cancerous hepatocytes with that in normal primary human hepatocytes and 37 dysregulated miRNAs were screened out by 2-fold change with a significant difference (P<0.05). Clustering analysis based on 13 miRNAs whose fold changes were over 15-fold change exhibited significantly differential expression pattern between the cancerous and normal hepatocytes.
2010-12-30 | E-GEOD-20077 | biostudies-arrayexpress
Project description:Sorafenib is currently the standard treatment for advanced hepatocellular carcinoma (HCC). Epigenetic alterations such as DNA methylation, play a decisive role in the development and progression of HCC. To our knowledge, there are no studies that have analyzed the global DNA methylation changes in HCC cells treated with sorafenib. Using MeDip-chip technologies we analyzed sorafenib effects on the methylome of human HCC cells. We found 1230 differentially methylated genes in HA22T/VGH cells treated with sorafenib compared to untreated cells. Gene ontology and pathway analysis found enriched several GO terms related to transcription factors and different pathways involved in tumorigenesis and cancer progression. Among the genes differentially methylated we found genes related to apoptosis (FOXO3, SMAD2, p21), angiogenesis (EPAS1) and invasion (MMP3, MMP7, RAC1, RHOC), genes belonged to pathways deregulated in HCC such as RAF/MEK/ERK (MAPK3, MAP2K2), JNK (MAPK8, MAP2K7), JAK-STAT (JAK1, STAT3, STAT5, CCND3), PI3K/AKT/mTOR (TSC2, PRKCZ) and NF-κB (IKBKG, MALT1, MAP3K14) and cancer-associated non-coding genes such as MALAT1, miR-149 and miR-675. We found a general trend where oncogenes were hypermethylated and tumor suppressor genes were hypomethylated after sorafenib treatment. Finally, we validated MeDip-chip results on several differentially methylated genes using COBRA and direct bisulfite sequencing and for these genes we evaluated the relationship between methylation level and mRNA expression.Our results suggest that in HCC cells sorafenib could affect the methylation level of genes associated to cancer-related processes and pathways related to sorafenib mechanism of action. These results identified novel sorafenib targets genes which could be targets in a new design of multi-target and combined therapies, and to better understand the emergence of resistance in HCC.
2017-06-30 | GSE72257 | GEO
Project description:Extensive loss of DNA methylation is a hallmark of cancer. The role of hypomethylation in altering gene expression in cancer cells has been poorly understood. Hepatic cellular carcinoma (HCC) is one of the most common human cancers. We use HCC as a model to investigate hypomethylation in cancer by a combination of methylated DNA immunoprecipitation and hybridization with comprehensive promoter arrays. We identify approximately 2,800 promoters that are hypomethylated in tumor samples. The hypomethylated promoters appear in clusters across the genome suggesting a high-level organization behind the epigenomic changes in cancer. The genes whose promoters are demethylated are mainly involved in cell growth, cell adhesion and communication, signal transduction, mobility and invasion; functions that are essential for cancer progression and metastasis. Previous studies suggested that MBD2 was involved in demethylation of uPA and MMP2 genes in human breast and prostate cancer cell lines. We extend these results here showing that whereas MBD2 depletion in normal liver cells has little or no effect, its depletion in the human hepatocellular carcinoma cell line HepG2 and the adenocarcinoma cell line SkHep1 results in suppression of cell growth, anchorage-independent growth and invasiveness, as well as an increase in promoter methylation and silencing of several of the genes that are hypomethylated in tumors. Our studies establish for the first time the rules governing hypomethylation of promoters in liver cancer and define the potential functional role of hypomethylation in cancer. Cancerous and normal adjacent tissue samples were obtained from 11 patients with HCC from the Chinese National Human Genome Center at Shanghai, China (Dr. Ze-Guang Han). For three patients, the cancer samples were dissected using laser capture microdissection technique. All patients provided written informed consent, and the Ethics Committee from the Chinese National Human Genome Center at Shanghai approved all aspects of this study. Human HCC HepG2 cells and adenocarcinoma SkHep1 cells were purchased from ATCC (HB8065 and HTB52, respectively, USA), whereas human untransformed hepatocytes (normal hepatocytes, NorHep) were obtained from Celprogen (33003-02, USA). Purified DNA from cancerous samples and normal adjacent samples, as well as HepG2 and NorHep cells, was enriched for methylated DNA using the MeDIP protocol developed by Cedar's group (PMID 16444255). The labeled input and bound DNA samples were hybridized to a custom-designed 244K promoter tiling array that contained probes covering all transcription start sites at intervals from 800 bp upstream to 200 bp downstream of all genes described in Ensembl (version 44) and within 250 bp of the ~400 microRNAs from miRBase, all at 100 bp-spacing.
2011-06-04 | E-GEOD-29720 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) are aberrant expressed in hepatocellular carcinoma (HCC) tissue and play a central role in diverse biological processes. We conducted a genome-wide miRNAs screening in 10 pairs of HCC tumor and adjacent non-tumor tissues to test the hypothesis that dysregulation of miRNAs in HCC tumor tissue are partially due to aberrant methylation in relevant miRNAs host genes. Taqman low density arrays were used to examine miRNA profiles in paired HCC tissues, and quantitative RT-PCR was used to validate candidate miRNAs for both discovery and validation sets. A cross-sectional study was conducted in 10 HCC tumor tissues and 10 adjacent non-tumor tissues in Columbia University Medical Center (CUMC), which is approved by the Institutional Review Board.
2014-02-08 | E-GEOD-54751 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE41048: Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues (ChIP-Seq and MeDIP-Seq) GSE41049: Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues (Gene Expression data) Refer to individual Series
2012-09-24 | E-GEOD-41050 | biostudies-arrayexpress
Project description:Early postnatal life is considered as a critical time window for determination of long-term metabolic states and organ functions. Extrauterine growth restriction (EUGR) causes the development of adult onset chronic diseases, including pulmonary arterial hypertension (PAH). However, the effects of nutritional disadvantages during early postnatal period on pulmonary vascular consequences in later life are not fully understood. Our study was designed to test whether epigentic dysregulation mediates the cellular memory of this early postnatal event. To test this hypothesis, we isolated pulmonary vascular endothelial cells (PVEC) by magnetic-activated cell sorting (MACS) from EUGR and control rats. A postnatal insult, nutritional restriction-induced EUGR caused development of an increased pulmonary artery pressure at 9-week of age in male rats. MeDIP-chip (Methyl-DNA immune precipitation chip), genome-scale mapping studies to search for differentially methylated loci between control and EUGR rats revealed significant difference in cytosine methylation between EUGR and control rats. We validated candidate dysregulated loci with quantitative assays of cytosine methylation and gene expressions. EUGR changes cytosine methylation at ~500 loci in male rats at 9 weeks of age, preceding the development of PAH and these represent candidate loci for mediating the pathogenesis of pulmonary vascular disease that occurs later in life. These results demonstrate that epigenetic dysregulation is a strong mechanism for propagating the cellular memory of early postnatal events, causing changes in expression of genes and long term susceptibility to PAH, and further providing a new insight into prevention and treatment of EUGR-related PAH. MeDIP together with microarray analysis demonstrated that significant differences in cytosine methylation between EUGR and control rats. Comparison of EUGR(n=3) vs Control (n=3) male rats' pulmonary vascular endothelial cells in 9-week age old rats
2013-07-10 | E-GEOD-48648 | biostudies-arrayexpress