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
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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: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:<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:Multiple carcinogenesis is one of the major characteristics of human hepatocellular carcinoma (HCC). The history of multiple tumors, i.e., whether they are derived from a common precancerous or cancerous ancestor or individually from hepatocytes, is a major issue. Multiple HCC is clinically classified into intratumor metastasis (IM) and multicentric carcinogenesis (MC). Molecular markers differentiating IM and MC are of interest to clinical practitioners because clinical diagnosis of IM and MC often leads to different therapies. We analyzed multiple HCCs for somatic mutations of cancer-related genes, chromosomal aberrations, and promoter methylation of tumor suppressor genes, using techniques such as high-resolution melting, array-comparative genomic hybridization (CGH), and quantitative methylation-specific PCR. Comparative genomic hybridizaion experiments. A total of 20 tumor samples: ten pairs of HCC (from ten patients).
2010-09-08 | E-GEOD-22635 | biostudies-arrayexpress
Project description:Gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from pre-neoplastic lesions (cirrhosis and dysplasia) to HCC, including four neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. Gene signatures that accurately reflect the pathological progression of disease at each stage were identified and potential molecular markers for early diagnosis uncovered. Pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then up-regulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages. Experiment Overall Design: 75 samples covering 8 stages of HCV induced HCC, with up to 13 biological repeats for each stage. Normal liver were used as control.
2008-06-15 | E-GEOD-6764 | biostudies-arrayexpress
Project description:Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which druggable alterations are uncommon, including hepatocellular carcinoma (HCC). We analyzed 377 HCC and 59 adjacent non-malignant liver tissue samples, focusing on alterations to component genes of the widely studied CRL2pVHL complex. Patient outcome was significantly worse when complex components VHL, CUL2, ELOC, or RBX1 were overexpressed in tumours. DNA hypomethylation and copy number increase were correlated with this overexpression, but many tumours had mRNA upregulation that was not explained by either mechanism. To assess the potential role of miRNA downregulation in component gene upregulation, we first acquired a wide-ranging view of the liver miRNA transcriptome by finding all miRNAs that were expressed in fetal liver, HCC, or adjacent non-malignant samples. Interestingly, we found 66 miRNAs, including 39 previously unannotated miRNAs, that were downregulated in HCC and predicted to target one or more CRL2pVHL components. Several miRNAs, including hsa-miR-101-3p and hsa-miR-139-5p, were negatively correlated with multiple component genes, suggesting that miRNA deregulation may contribute to CRL2pVHL overexpression. Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2pVHL complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms. A better understanding of the CRL2pVHL components and further elucidation of their regulation could expand our understanding of HCC oncogenesis and aid in the development of novel inhibitors.
2022-06-21 | GSE194052 | GEO
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:Gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from pre-neoplastic lesions (cirrhosis and dysplasia) to HCC, including four neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. Gene signatures that accurately reflect the pathological progression of disease at each stage were identified and potential molecular markers for early diagnosis uncovered. Pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then up-regulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages. Keywords: 8 pathological stages of HCV-induced HCC
2007-06-21 | GSE6764 | GEO
Project description:Epigenetic changes commonly occur in hepatocellular carcinoma (HCC) and are associated with aberrant gene expression. Recently, we demonstrated the pivotal role of abnormal H3K4me3 methylation, which is catalyzed by the menin/MLL, a TrxG family, in HCC development. Meanwhile, there is clear evidence that increasing global levels of H3K27me3 are activated in human primary HCC. To further elucidate the functional relatedness of the active H3K4me3 and repressive H3K27me3 histone remodeling in HCC, we performed H3K4me3 and H3K27me3 ChIP-on-chip screen using three HCC specimens and their adjacent tissues. Comparison of ChIP-on-chip results between tumor(C) and adjacent tissues(N) from three HCC specimens with H3K4me3
2013-11-08 | E-GEOD-52190 | biostudies-arrayexpress
Project description:Epigenetic changes commonly occur in hepatocellular carcinoma (HCC) and are associated with aberrant gene expression. Recently, we demonstrated the pivotal role of abnormal H3K4me3 methylation, which is catalyzed by the menin/MLL, a TrxG family, in HCC development. Meanwhile, there is clear evidence that increasing global levels of H3K27me3 are activated in human primary HCC. To further elucidate the functional relatedness of the repressive H3K27me3 and active H3K4me3 histone remodeling in HCC, we performed H3K27me3 and H3K4me3 ChIP-on-chip screen using three HCC specimens and their adjacent tissues. Comparison of ChIP-on-chip results between tumor(C) and adjacent tissues(N) from three HCC specimens with H3K27me3
2013-11-13 | E-GEOD-52301 | biostudies-arrayexpress