Browsing by Subject "Epigenetic"

Now showing 1 - 6 of 6
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    Epigenetic modulation of differentiation in CE44 teratocarcinoma
    (Murcia : F. Hernández, 1999) Álvarez, A.; Lacalle, J.; Garcia-Sanz, M.; Simón, J.; Aréchaga, J.; Hilario, E.
    Teratocarcinoma is a mixed germ cell tumor histologically composed of embryonal carcinoma cells and embryonic and extraembryonic tissues. In the present work we have used the CE44 teratocarcinoma, which is a tumor cell line derived from the OTT6050 experimental tumor, to appreciate the influence the microenvironment has on the modulation of tumoral differentiation. For this, we have studied the development of CE44 teratocarcinoma in primary tumors (subcutaneous and intrasplenic) and in experimental metastases (hepatic and pulmonary). CE44 teratocarcinoma shows variations in its capacity for differentiation in so far as development is concerned and, in hepatic metastases, we noticed a reparative process of the intratumoral necrotic areas which in the same cases were substituted by loose connective tissue. Our results clearly suggest that the microenvironment is decisive in the biological behaviour of the teratocarcinoma cells and that epigenetic factors influence the capacity for differentiation of the undifferentiated tumoral cells.
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    Identification of transcriptomic and associated DNA methylation changes Induced by the oocyte In vitro maturation in pig
    Abril-Parreño, Laura; Lopes, Jordana S.; Galvao, Antonio; Kelsey, Gavin; Coy, Pilar; Fisiología
    In humans, oocyte in vitro maturation (IVM) is an assisted reproductive technique used for patients with a high antral follicle count, polycystic ovary syndrome, and fertility preservation in cancer. In other cases, controlled ovarian hyperstimulation allowing in vivo maturation is the preferred method since it yields higher success rates. However, increasing evidence has revealed that hyperstimulation can lead to perturbed genomic imprinting and DNA methylation, which may impair offspring health. Therefore, IVM should be considered an alternative technique, but it is yet to be determined if similar epigenetic alterations also occur. Here we used the pig as a model to investigate the potential impacts of IVM on gene expression and DNA methylation in oocytes. To account for such variation, we used single-cell bisulphite sequencing and single-cell RNA sequencing techniques. The study was performed on 20 porcine oocytes obtained after IVM and 20 in vivo matured oocytes obtained by ovum pick-up from ex vivo ovaries. Differentially expressed genes (DEGs: P < 0.05, FC > 1.5) and differentially methylated regions (DMRs, P < 0.05, FC > 0.1) were determined and functionally annotated using Bioconductor packages in R. For the integration of both omics datasets, the single-cell aggregation and integration tool was used and a P < 0.05 and FC > 0.25 was applied to consider the interaction significant. Using the in vivo group as a reference, 1297 and 476 DEGs were down-regulated and up-regulated, respectively, in the IVM group. The up-regulated DEGs in IVM oocytes were mainly associated with the regulation of organelle organization, DNA methylation, and cell cycle processes; down-regulated genes were mainly enriched in ribosomal RNA processing, protein synthesis, oxidative phosphorylation and metabolomic processes such as glycosyl and aldehyde compound pathways. The global percentage of methylation was similar between the IVM and in vivo groups, but 321, 344, and 843 DMRs were detected (P < 0.05) in CpG islands, promoters and coding regions, respectively. Notably, the germline differentially regions of imprinted genes were appropriately methylated irrespective of IVM. Integrative analysis of DNA methylation and RNA-seq data identified the main methylated regions and genes that define each group. A total of 236 loci and 296 genes defined the IVM group, while 856 loci and 688 genes were related to the in vivo group. In addition, in the IVM group, we found a higher number of negative correlations between gene expression and DNA methylation, while the in vivo group showed higher number and stronger positive correlations. Taken together, these results indicate a discrete effect of IVM on the DNA methylation landscape in mature porcine oocytes, but these changes seem to have a greater impact on gene expression regulation.
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    PRMT1-dependent methylation of BRCA1 contributes to the epigenetic defense of breast cancer cells against ionizing radiation
    (Springer Nature, 2020-08-06) González Guerrero, Rebeca; Piñero Madrona, Antonio; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
    The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; however, resistant cells rapidly initiate mechanisms to repair such damage. While DNA repair mechanisms responsible for cancer cell survival following DNA damage are understood, less is known about the epigenetic mechanisms resulting in resistance to radiotherapy. Although changes in DNA methylation are related to mechanisms of long-term resistance, it is more likely that the methylation state of a series of proteins could be responsible for the first-line of defense of cancer cells against irradiation. In this study, we observed that irradiation of breast cancer cells was accompanied by an overproduction in S-adenosylmethionine, which increases the activity of cellular methylases. We found that by activating PRMT1, irradiation triggers a BRCA1-dependent program that results in efficient DNA repair and inhibition of apoptosis. Depletion of PRMT1 in irradiated cells resulted in a switch of BRCA1 functions from repair and survival in the nucleus to activation of cell death signals in the cytoplasm. We conclude that by modulating the cellular localization of BRCA1, PRMT1 is an important regulator of the oncogenic functions of BRCA1, contributing to the epigenetic defense of breast cancer cells against ionizing radiation.
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    Targeting the epigenetic machinery of cancer cells
    (Springer Nature, 2014-01-27) Fernández Pérez, María Piedad; Sáez Ayala, Magalí; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
    Cancer is characterised by uncontrolled cell growth and the acquisition of metastatic properties. In most cases, the activation of oncogenes and/or deactivation of tumour suppressor genes lead to uncontrolled cell cycle progression and inactivation of apoptotic mechanisms. Although the underlying mechanisms of carcinogenesis remain unknown, increasing evidence links aberrant regulation of methylation to tumourigenesis. In addition to the methylation of DNA and histones, methylation of non-histone proteins, such as transcription factors, is also implicated in the biology and development of cancer. Because the metabolic cycling of methionine is a key pathway for many of these methylating reactions, strategies to target the epigenetic machinery of cancer cells could result in novel and efficient anti-cancer therapies. The application of these new epigenetic therapies could be of utility to promote E2F1-dependent apoptosis in cancer cells, avoid metastatic pathways and/or sensitise tumour cells to radiotherapy.
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    Targeting the epigenetics of the DNA damage response in breast cancer
    (Springer Nature, ) González Guerrero, Rebeca; Piñero Madrona, Antonio; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
    Cancer is as much an epigenetic disease as it is a genetic disease, and epigenetic alterations in cancer often serve as potent surrogates for genetic mutations. Because the epigenetic factors involved in the DNA damage response are regulated by multiple elements, therapies to target specific components of the epigenetic machinery can be inefficient. In contrast, therapies aimed at inhibiting the methionine cycle can indirectly inhibit both DNA and protein methylation, and the wide variety of genes and pathways that are affected by these methylations make this global strategy very attractive. In the present study, we propose an adjuvant therapy that targets the epigenetics of the DNA damage response in breast cancer cells and that results in efficient apoptosis and a reduction in distant metastases in vivo. We observed that a combined therapy designed to uncouple adenosine metabolism using dipyridamole in the presence of a new synthetic antifolate, 3-O-(3,4,5-trimethoxybenzoyl)-(−)-catechin, simultaneously and efficiently blocked both the folic cycle and the methionine cycle in breast cancer cells and sensitized these cells to radiotherapy. The treatment impeded the recruitment of 53BP1 and BRCA1 to the chromatin regions flanking DNA double-strand breaks and thereby avoided the DNA damage responses in breast cancer cells that were exposed to ionizing radiation. In addition, this hypomethylating therapy was also efficient in reducing the self-renewal capability of breast cancer-initiating cells and induced reversion of mesenchymal phenotypes in breast cancer cells
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    Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis
    (Springer Nature, 2016-05-02) Gonzalez Guerrero, Rebeca; Martínez Barba, Enrique; Piñero Madrona, Antonio; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
    During the course of cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, and this plasticity is enabled by underlying shifts in epigenetic regulation. Our results identified a negative feedback loop in which SET9 controls DNA methyltransferase-1 protein stability, which represses the transcriptional activity of the SET9 promoter in coordination with Snail. The modulation of SET9 expression in breast cancer cells revealed a connection with E2F1 and the silencing of SET9 was sufficient to complete an epigenetic program that favored epithelial–mesenchymal transition and the generation of cancer stem cells, indicating that SET9 plays a role in modulating breast cancer metastasis. SET9 expression levels were significantly higher in samples from patients with pathological complete remission than in samples from patients with disease recurrence, which indicates that SET9 acts as a tumor suppressor in breast cancer and that its expression may serve as a prognostic marker for malignancy