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Integrative analysis of gene expression and DNA methylation reveals epigenetic regulation of tumor suppressor genes and oncogenes involved in uterine leiomyoma pathogenesis [Methyl-Seq]

ABSTRACT: Uterine leiomyomas (UL) are the most common benign tumors in women of reproductive age. Despite the high prevalence, its pathology remains unclear, which hampers the development of safe and effective treatments. Several works have pointed the involvement of epigenetic mechanisms in UL development. Specifically, DNA methylation plays an important role in gene expression regulation. We aim to determine the relationship between DNA methylation and gene expression in UL compared to adjacent myometrium (MM) to describe molecular mechanisms involved in UL formation that are under epigenetic control. Our results showed a different DNA methylation profile between UL and MM, leading to hypermethylation of UL, as well as a different global transcriptome profile. Integration of DNA methylation and transcriptome data resulted in 93 genes regulated by methylation, 22 hypomethylated/upregulated and 71 hypermethylated/downregulated. Functional enrichment analysis showed dysregulated biological processes involved in metabolism and cell physiology, response to extracellular signals, invasion, and proliferation in UL. Cellular components as cell membranes, vesicles, extracellular matrix, and cell junctions were dysregulated in UL. In addition, we found hypomethylation/upregulation of oncogenes (PRL, ATP8B4, CEMIP, ZPMS2-AS1) and hypermethylation/downregulation of tumor suppressor genes (EFEMP1, FBLN2, ARHGAP10, HTATIP2) in UL, which were related to proliferation, invasion, altered metabolism, deposit of extracellular matrix and Wnt/β-catenin pathway dysregulation. This confirms that key processes of UL development are under DNA methylation control. Finally, 5-aza-CdR treatment increased expression of hypermethylated/downregulated genes in UL cells. In conclusion, DNA methylation gene regulation is implicated in UL pathogenesis, and its reversion could be a potential therapeutic option.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192353 | GEO | 2022/05/31

REPOSITORIES: GEO

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Project description:Background: Human bone marrow mesenchymal stem cells (MSCs) expanded in vitro exhibit not only a tendency to lose their proliferative potential, homing ability and telomere length but also genetic or epigenetic modifications such as DNA methylation and the noncoding RNA-mediated mechanism. This results in the senescence of MSCs. We compared differential methylation patterns of genes and miRNAs between early-passage and late-passage cells and estimated the relationship between senescence and DNA methylation patterns. Genomic DNA of MSCs cultured at passage 5 (P5) and passage 15 (P15) was enriched using methylated DNA immunoprecipitation assays, and DNA methylation changes due to long-term culture of MSCs were analyzed using Human 2.1M Deluxe Promoter Arrays (NimbleGen). Results: When we analyzed the methylation differences between P5 and P15 more than twice, 3,338 genes showed more than two-fold higher methylation at P5 than P15, whereas 4,670 genes showed more than two-fold higher methylation at P15 than P5. When we examined hypermethylated genes (methylation peak ≥ 2) at P5 or P15, 2,739 genes, including those related to fructose and mannose metabolism and calcium signaling pathways, and 2,587 genes, including those related to DNA replication, cell cycle and the PPAR signaling pathway, were hypermethylated at P5 and P15, respectively. There was common hypermethylation of 1,205 genes at both P5 and P15. In addition, genes that were hypermethylated at P5 (CPEB1, GMPPA, CDKN1A, TBX2, SMAD9 and MCM2) showed lower mRNA expression than did those hypermethylated at P15, whereas genes that were hypermethylated at P15 (MAML2, FEN1 and CDK4) showed lower mRNA expression than did those that were hypermethylated at P5, demonstrating that hypermethylation at DNA promoter regions inhibited gene expression and that hypomethylation increased gene expression. In the case of hypermethylation on miRNA, 27 miRNAs were hypermethylated at P5, whereas 44 miRNAs were hypermethylated at P15. Conclusion: These results show that hypermethylation increases at genes related to DNA replication, cell cycle and adipogenic differentiation due to long-term culture, which may in part affect MSC senescence.

Project description:Background an Aim: Epigenetics are thought to play a major role in the carcinogenesis of patients that develop multiple colorectal cancers (CRC) in the non-hereditary setting. Previous studies have suggested concordant DNA hypermethylation between tumor pairs. However, only a few methylation markers have been analyzed. This study was aimed at describing the underlying epigenetic signature that differentiates multiple from solitary colorectal cancer tumors using a genome-scale DNA methylation profiling. Patients and Methods: We used a population-based cohort (EPICOLON II) of 12 patients with synchronous CRC and 29 age- sex- and tumor location-paired solitary CRC patients. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay. The most significantly hypermethylated CpG sites results were validated by Methylight. Tumors samples were also analyzed for the CpG Island Methylator Phenotype (CIMP) using the Infinium DNA methylation data; KRAS and BRAF mutations; microsatellite instability; and immunohistochemistry for MLH1/MSH2/MSH6/PMS2. Functional annotation clustering of differentially methylated genes between multiple and solitary CRCs was performed. Results: We identified 102 CpG sites that showed significant DNA hypermethylation in multiple versus solitary tumors (difference in M-NM-2 value >0.1 and p<0.05). Methylight assays validated the array results for 4 selected significantly hypermethylated genes (MAP1B, HTRA1, ALOX15, TIMP3) identified in the profiling (p=0.0002). Based on the Infinium data, 8/12 (66.6%) of multiple tumors were classified as CIMP-high, as compared to 5/29 (17%) solitary tumors (p=0.004). CIMP-high tumors displayed significant hypermethylation in 301 CpG sites (difference in M-NM-2 value >0.1; p value <0.05). Interestingly, 76/102 (74.5%) of the hypermethylated CpG sites found in multiple vs. solitary tumors were also seen to be hypermethylated in CIMP-H tumors. Functional analysis of hypermethylated genes found in multiple vs. solitary tumors showed the presence and enrichment of genes involved in different tumorigenic functions. Conclusions: Multiple colorectal cancers are associated with a distinct methylation phenotype, with a close association between tumor multiplicity and CIMP-high. Our results may be important to unravel the underlying mechanism of tumor multiplicity in the non-hereditary scenario, and provide novel potential biomarkers for identifying high-risk patients and tailoring surveillance strategies. We used a population-based cohort (EPICOLON II) of 12 patients with synchronous CRC and 29 solitary CRC patients. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay.

Project description:Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints involved with genetic and epigenetic aberrant. Recent evidence found more and more importance of the epigenetic contribution, especially the DNA methylation, to the pathogenesis of rheumatoid arthritis. To understand the extent and nature of dysregulated DNA methylation in rheumatoid arthritis T cells, we performed a genome-wide DNA methylation study in CD4+ T cells in 12 rheumatoid arthritis patients compared to 12 matched normal healthy controls. [Methods and Result] Cytosine methylation status was quantified with Illumina methylation 450K microarray (HM450K, 485512 CpG sites). We identified 810 hypomethylated and 392 hypermethylated CG sites in RA CD4+ T cells compared to normal controls, representing 383 and 785 genes hypermethylated and hypomethylated in RA patients (P<3.4*10-7). Cluster analysis based on significantly differential methylated loci showed distinct separation between RA and normal controls. Gene ontology analysis showed alternative splicing (P=1.2*10-7, FDR) and phosphoprotein (1.7*10-2, FDR) were significantly aberrant in RA patients, indicating the abnormal of transcript alternative splicing and protein modification mediated by DNA methylation might play important role in the pathogenesis of rheumatoid arthritis. What’s more, the result showed human leukocyte antigen (HLA) region was frequently hypomethylated in RA patients, including HLA-DRB6, HLA-DQA1 and HLA-E, however, HLA-DQB1 showed different methylation profiles with significant hypermethylation in CpG island region and hypomethylation in CpG shelf region. Outsite of the MHC region, the most hypermethylated genes in RA included HDAC4, NXN, TBCD and TMEM61 while the most significant hypomethylated genes included ITIH3, TCN2, PRDM16, SLC1A5 and GALNT9. [Conclusion] Genome-wide DNA methylation patterns revealed significant DNA methylation change in CD4+ T cells from patients with rheumatoid arthritis. 12 rheumatoid arthritis and 12 matched health individuals

Project description:Background an Aim: Epigenetics are thought to play a major role in the carcinogenesis of patients that develop multiple colorectal cancers (CRC) in the non-hereditary setting. Previous studies have suggested concordant DNA hypermethylation between tumor pairs. However, only a few methylation markers have been analyzed. This study was aimed at describing the underlying epigenetic signature that differentiates multiple from solitary colorectal cancer tumors using a genome-scale DNA methylation profiling. Patients and Methods: We used a population-based cohort (EPICOLON II) of 12 patients with synchronous CRC and 29 age- sex- and tumor location-paired solitary CRC patients. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay. The most significantly hypermethylated CpG sites results were validated by Methylight. Tumors samples were also analyzed for the CpG Island Methylator Phenotype (CIMP) using the Infinium DNA methylation data; KRAS and BRAF mutations; microsatellite instability; and immunohistochemistry for MLH1/MSH2/MSH6/PMS2. Functional annotation clustering of differentially methylated genes between multiple and solitary CRCs was performed. Results: We identified 102 CpG sites that showed significant DNA hypermethylation in multiple versus solitary tumors (difference in β value >0.1 and p<0.05). Methylight assays validated the array results for 4 selected significantly hypermethylated genes (MAP1B, HTRA1, ALOX15, TIMP3) identified in the profiling (p=0.0002). Based on the Infinium data, 8/12 (66.6%) of multiple tumors were classified as CIMP-high, as compared to 5/29 (17%) solitary tumors (p=0.004). CIMP-high tumors displayed significant hypermethylation in 301 CpG sites (difference in β value >0.1; p value <0.05). Interestingly, 76/102 (74.5%) of the hypermethylated CpG sites found in multiple vs. solitary tumors were also seen to be hypermethylated in CIMP-H tumors. Functional analysis of hypermethylated genes found in multiple vs. solitary tumors showed the presence and enrichment of genes involved in different tumorigenic functions. Conclusions: Multiple colorectal cancers are associated with a distinct methylation phenotype, with a close association between tumor multiplicity and CIMP-high. Our results may be important to unravel the underlying mechanism of tumor multiplicity in the non-hereditary scenario, and provide novel potential biomarkers for identifying high-risk patients and tailoring surveillance strategies.

Project description:Introduction: Hepatocellular carcinoma (HCC) is one of the most aggressive solid tumors and oncogenic pathways (e.g Akt, IGF signaling) are often activated in high proliferating HCC. Among several genetic alterations, epigenetic changes seem to be involved in the development and progression of HCC. DNA hypermethylation of promoter regions is almost always associated with transcriptional silencing and can lead to inactivation of tumor suppressor genes (TSG) in cancer cells. Aim: (1) To identify genes differently methylated in a subclass of HCC associated with proliferation and, (2) To correlate methylation changes with activation of molecular pathways. Methods: gDNA of 20 HCC, 8 cirrhotic and 8 normal liver samples was extracted and the methylation status was detected by the Illumina HumanMethylation27 BeadChip and immunohistochemistry of p-AKT, pIGF IR, p-S6 was analyzed. Results: Unsupervised clustering clearly classified normal livers, cirrhosis and HCC in 3 different groups. 961 genes were significantly hypermethylated in HCC compared to cirrhotic and 3942 genes showed hypermethylation in cirrhotic compared to normal liver tissue. 163 genes showed stepwise significant hypermethylation from normal to cirrhotic to HCC, including well described (p16, SOCS2, SFRP5, RBP1) and potential (SRD5A2, PCDH8, IGF-1R, UCHL1) TSGs, and the miR-10a. 133 genes were specifically hypermethylated in HCC. Among them the transcription factors GATA2, DLX1, and KLF14, all significantly inversely correlated to gene expression (p=0.003, p=0.03, and p=0.007, respectively). The methylation status of SOCS2 (p=0.025) and DLX1 (p=0.025) was significantly correlated to phosphorylation of IGFR1. Samples with RBP1 hypermethylation showed significantly higher AFP serum levels (p=0.018). Conclusion: Whole genome methylation analysis markedly classifies normal, cirrhotic and HCC samples. 8 TSGs play a key role in this stepwise progression of hypermethylation in the development of HCC and could be a promising point of action in anticancer therapy. Genomic DNA extracted from fresh frozen tissue specimens and cell lines was hybridized to genome-wide mthylation beadarray after bisulphite treatment. Keywords: DNA methylation, hepatocellular carcinoma, tissue, cell line

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Integrative analysis of gene expression and DNA methylation reveals epigenetic regulation of tumor suppressor genes and oncogenes involved in uterine leiomyoma pathogenesis [Methyl-Seq]

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