Integrative analysis of gene expression and DNA methylation reveals epigenetic regulation of tumor suppressor genes and oncogenes involved in uterine leiomyoma pathogenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE192354 | GEO | 2022/05/31
REPOSITORIES: GEO
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Project description: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.
2022-05-31 | GSE192352 | GEO
Project description: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.
2022-05-31 | GSE192353 | GEO
Project description:Integrative analysis of gene expression and DNA methylation reveals epigenetic regulation of tumor suppressor genes and oncogenes involved in uterine leiomyoma pathogenesis
| PRJNA791228 | ENA
Project description:Integrative analysis of gene expression and DNA methylation reveals epigenetic regulation of tumor suppressor genes and oncogenes involved in uterine leiomyoma pathogenesis [Methyl-Seq]
| PRJNA791235 | ENA
Project description:Integrative analysis of gene expression and DNA methylation reveals epigenetic regulation of tumor suppressor genes and oncogenes involved in uterine leiomyoma pathogenesis [RNA-seq]
| PRJNA791231 | ENA
Project description:Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here, we report the elucidation of the biological characteristics of the two most prevalent uterine leiomyoma subtypes, MED12-mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) uterine leiomyomas. Because each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-uterine leiomyoma were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of extracellular matrix in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both uterine leiomyoma subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these uterine leiomyoma subtypes emphasize the importance of subtypes and genotypes in designing nonsurgical therapeutic strategies for uterine leiomyoma. Cancer Res; 77(24); 6891-901. ©2017 AACR.
| S-EPMC6015476 | biostudies-literature
Project description:NAV 3 is a tumor suppressor of unknown function in leiomyomas. The objective of this study is to assess NAV3 expression and its potential role in human uterine leiomyomas. NAV3 protein expression was examined in patient leiomyoma and patient-matched myometrial tissue samples by Western blot and immunohistochemistry. NAV3 mRNA and protein expression was assessed in leuprolide acetate- and cetrorelix-treated cell line leiomyoma samples. RNAseq analysis of placebo-treated leiomyoma compared with myometrium demonstrated the presence of transcripts encoding for several neuronal proteins. For NAV3, RNA sequence analysis demonstrated decreased expression in leiomyoma as compared with myometrium (0.86 ± 0.03 fold). Presence of NAV3 mRNA was also decreased in leiomyoma surgical samples (0.43 fold ± 0.05, p = 0.026) compared with patient-matched myometrium. Confirmatory qRT-PCR results on immortalized leiomyoma and myometrial cell lines similarly demonstrated a decrease in expression of NAV3 in leiomyomas (0.28 ± 0.02, p = 0.00075). Immunohistochemical analysis demonstrated a significant decrease in NAV 3 protein in leiomyomas (H-score 154.7 ± 6.2) as compared with myometrium (H-score; 312.5 ± 14.7, p < 0.0001). Leuprolide acetate-treated leiomyoma cells demonstrated an increase in NAV 3 mRNA expression (1.53 ± 0.13, p < 0.0001). Similarly, Western blot analysis on leuprolide-treated leiomyoma cells showed a non-significant increase in NAV 3 protein expression (1.26 ± 0.09, p = 0.063). NAV 3, a tumor suppressor in numerous cancers, is decreased in leiomyoma cells and tissue compared with myometrium, and increased by GnRH analog treatment, suggesting that NAV3 may mediate steroid hormone-independent leiomyoma regulation by GnRH analogs.
| S-EPMC7539815 | biostudies-literature
Project description:BackgroundUterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown.Principal findingsWe characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels.ConclusionsThese results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women.
| S-EPMC3302826 | biostudies-literature
Project description:Data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. Here, we developed an algorithm, DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), to identify TSGs and OGs by integrating comprehensive genetic and epigenetic data. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancers, and methylation differences as strong predictors for OGs. We extensively validated DORGE-predicted cancer driver genes using independent functional genomics data. We also found that DORGE-predicted dual-functional genes (both TSGs and OGs) are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed previously undetected cancer driver genes.
| S-EPMC7673741 | biostudies-literature
Project description:MotivationFunctions of cancer driver genes vary substantially across tissues and organs. Distinguishing passenger genes, oncogenes (OGs) and tumor-suppressor genes (TSGs) for each cancer type is critical for understanding tumor biology and identifying clinically actionable targets. Although many computational tools are available to predict putative cancer driver genes, resources for context-aware classifications of OGs and TSGs are limited.ResultsWe show that the direction and magnitude of somatic selection of protein-coding mutations are significantly different for passenger genes, OGs and TSGs. Based on these patterns, we develop a new method (genes under selection in tumors) to discover OGs and TSGs in a cancer-type specific manner. Genes under selection in tumors shows a high accuracy (92%) when evaluated via strict cross-validations. Its application to 10 172 tumor exomes found known and novel cancer drivers with high tissue-specificities. In 11 out of 13 OGs shared among multiple cancer types, we found functional domains selectively engaged in different cancers, suggesting differences in disease mechanisms.Availability and implementationAn R implementation of the GUST algorithm is available at https://github.com/liliulab/gust. A database with pre-computed results is available at https://liliulab.shinyapps.io/gust.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC7703750 | biostudies-literature