Biology subjects

Cuenin, C.

Publications and source records attributed to Cuenin, C..

6 recordsLinked to original sources

bioRxiv2024

Disruption of the epigenetic regulator BAP1 drives chromatin remodeling leading to the emergence of cells with breast cancer stem cell properties and aberrant glycosylation.

BackgroundEpigenetic regulator genes play critical roles in controlling cell identity and are frequently disrupted in breast cancers, suggesting a key driver role in this disease and its associated phenotypes. However, specific epigenetic drivers (epidrivers) of mammary cell plasticity and their mechanistic contributions to this phenotype are poorly characterized. MethodsTo identify potential epidrivers of the emergence of mesenchymal breast cancer stem cell-like phenotypes in non-tumorigenic mammary cells, we employed a CRISPR/Cas9 loss-of-function screening strategy targeting epigenetic regulator genes. This approach was followed by an in-depth validation and characterization of epigenomic, transcriptomic, proteomic and phenotypic changes resulting from the disruption of the putative epidriver gene BAP1. ResultsOur investigation revealed that loss of the histone deubiquitinase BAP1 impacts cellular processes associated with breast cancer cell plasticity such as epithelial-to-mesenchymal transition (EMT) and actin cytoskeleton organization. In addition, we unveiled that BAP1 loss resulted in an overall less permissive chromatin and downregulated gene expression, impacting programs that control cellular glycosylation and leading to decreased glycan abundance and complexity. BAP1 rescue restored the expression of several deregulated genes in a catalytic activity-dependent manner, suggesting that BAP1-mediated cell identity and glycosylation regulation are largely dependent on its histone deubiquitinase activity. ConclusionsOverall, our results point to BAP1 disruption as a driver of mammary cell plasticity and reveal a novel role of BAP1 as an epigenetic regulator of cellular glycosylation.

cancer biology↗

bioRxiv2024

Molecular and cell phenotype programs in oral epithelial cells directed by co-exposure to arsenic and smokeless tobacco

Chronic arsenic exposure can lead to various health issues, including cancer. Concerns have been mounting about the enhancement of arsenic toxicity through co-exposure to various prevalent lifestyle habits. Smokeless tobacco products are commonly consumed in South Asian countries, where their use frequently co-occurs with exposure to arsenic from contaminated groundwater. To decipher the in vitro molecular and cellular responses to arsenic and/or smokeless tobacco, we performed temporal multi-omics analysis of the transcriptome and DNA methylome remodelling in exposed hTERT-immortalized human normal oral keratinocytes (NOK), as well as arsenic and/or smokeless tobacco genotoxicity and mutagenicity investigations in NOK cells and in human p53 knock-in murine embryonic fibroblasts (Hupki MEF). RNAseq results from acute exposures to arsenic alone and in combination with smokeless tobacco extract revealed upregulation of genes with roles in cell cycle changes, apoptosis and inflammation responses. This was in keeping with global DNA hypomethylation affecting genes involved in the same processes in response to chronic treatment in NOK cells. At the phenotypic level, we observed a dose-dependent decrease in NOK cell viability, induction of DNA damage, cell cycle changes and increased apoptosis, with the most pronounced effects observed under arsenic and SLT co-exposure conditions. Live-cell imaging experiments indicated that the DNA damage likely resulted from induction of apoptosis, an observation validated by a lack of exome-wide mutagenesis in response to chronic exposure to arsenic and/or smokeless tobacco. In sum, our integrative omics study provides novel insights into the acute and chronic responses to arsenic and smokeless tobacco (co-)exposure, with both types of responses converging on several key mechanisms associated with cancer hallmark processes. The generated rich catalogue of molecular programs in oral cells regulated by arsenic and smokeless tobacco (co-)exposure may provide bases for future development of biomarkers for use in molecular epidemiology studies of exposed populations at risk of developing oral cancer.

cancer biology↗

bioRxiv2021

Disentangling heterogeneity of Malignant Pleural Mesothelioma through deep integrative omics analyses

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Using the largest series of whole-genome sequencing data integrated with transcriptomic and epigenomic data using multi-omic factor analysis, we demonstrate that MPM heterogeneity arises from four sources of variation: tumor cell morphology, ploidy, adaptive immune response, and CpG island methylator phenotype. Previous genomic studies focused on describing only the tumor cell morphology factor, although we robustly find the three other sources in all publicly available cohorts. We prove how these sources of variation explain the biological functions performed by the cancer cells, and how genomic events shape MPM molecular profiles. We show how these new sources of variation help understand the heterogeneity of the clinical behavior of MPM and drug responses measured in cell lines. These findings unearth the interplay between MPM functional biology and its genomic history, and ultimately, inform classification, prognostication and treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/461908v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@b6c43corg.highwire.dtl.DTLVardef@10d45a9org.highwire.dtl.DTLVardef@58746eorg.highwire.dtl.DTLVardef@143f880_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

A protocol for good quality genomic DNA isolation from formalin-fixed paraffin-embedded tissues without using commercial kits

DNA isolation from formalin-fixed paraffin-embedded (FFPE) tissues for molecular analysis has become a frequent procedure in cancer research. However, the yield or quality of the isolated DNA is often compromised, and commercial kits are used to overcome this to some extent. We developed a new protocol (IARCp) to improve better quality and yield of DNA from FFPE tissues without using any commercial kit. To evaluate the IARCps performance, we compared the quality and yield of DNA with two commercial kits, namely NucleoSpin(R) DNA FFPE XS (MN) and QIAamp DNA Micro (QG) isolation kit. Total DNA yield for QG ranged from 120.0 - 282.0 ng (mean 216.5 ng), for MN: 213.6 - 394.2 ng (mean 319.1 ng), and with IARCp the yield was much higher ranging from 775.5 - 1896.9 ng (mean 1517.8 ng). Moreover, IARCp has also performed well in qualitative assessments. Overall, IARCp represents a novel approach to DNA isolation from FFPE which results in good quality and significant amounts of DNA suitable for many downstream genome-wide and targeted molecular analyses. Our proposed protocol does not require the use of any commercial kits for isolating DNA from FFPE tissues, making it suitable to implement in low-resource settings such as low and middle-income countries (LMICs).

cancer biology↗

bioRxiv2020

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption

Coffee and tea are extensively consumed beverages worldwide. Observational studies have shown contradictory findings for the association between consumption of these beverages and different health outcomes. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. We conducted epigenome-wide association studies (EWAS) on coffee and tea consumptions in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis revealed 11 CpG sites significantly associated with coffee consumption (P-value <1.1x10-7), nine of them annotated to the genes AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH, and two CpGs suggestively associated with tea consumption (P-value<5.0x10-6). Among these, cg14476101 was significantly associated with expression of its annotated gene PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells showed a correlation with expression levels of lipid-associated genes, suggesting a role of PHGDH in hepatic-lipid metabolism. Collectively, this study indicates that coffee consumption is associated with differential DNA methylation levels at multiple CpGs, and that coffee-associated epigenetic variations may explain the mechanism of action of coffee consumption in conferring disease risk.

genomics↗

bioRxiv2018

Interplay between the epigenetic enzyme lysine (K)-specific demethylase 2B and Epstein-Barr virus infection.

Histone modifier lysine (K)-specific demethylase 2B (KDM2B) plays a role in hematopoietic cells differentiation and its expression appears to be deregulated in certain cancers of hematological and lymphoid origins. We have previously found that KDM2B gene is differentially methylated in cell lines derived from the Epstein-Barr virus (EBV) associated endemic Burkitts lymphomas (eBL) compared to EBV negative sporadic BL cells. However, whether KDM2B plays a role in eBL development has never been previously demonstrated. Oncogenic viruses have been shown to hijack the host cell epigenome to complete their life cycle and to promote the transformation process by perturbing cell chromatin organization. Here we investigated whether EBV would alter KDM2B levels to enable its life cycle and promote B-cells transformation. We show that infection of B-cells with EBV leads to down-regulation of KDM2B levels. We also show that LMP1, one of the main EBV transforming proteins, induces increased DNMT1 recruitment to KDM2B gene and augments its methylation. By altering KDM2B levels and performing chromatin immunoprecipitation in EBV infected B-cells, we were able to show that KDM2B is recruited to the EBV gene promoters and inhibits their expression. Furthermore, forced KDM2B expression in immortalized B-cells led to altered mRNA levels of some differentiation-related genes. Our data show that EBV deregulates KDM2B levels through an epigenetic mechanism and provide evidence for a role of KDM2B in regulating virus and host cell gene expression, warranting further investigations to assess the role of KDM2B in the process of EBV-mediated lymphomagenesis.\n\nIMPORTANCE. In Africa, Epstein-Barr virus infection is associated with endemic Burkitt lymphoma, a pediatric cancer. The molecular events leading to its development are poorly understood compared to the sporadic Burkitt lymphoma. In a previous study, by analyzing the DNA methylation changes in endemic compared to sporadic Burkitt lymphomas cell lines, we identified several differential methylated genomic positions in proximity of genes with a potential role in cancer, among them the KDM2B gene. KDM2B encodes a histone H3 demethylase already shown to be involved in some hematological disorders. However, whether KDM2B plays a role in the development of Epstein-Barr virus-mediated lymphoma has never been investigated before. In this study we show that Epstein-Barr virus deregulates KDM2B expression and describe the underlying mechanisms. We also reveal a role of the demethylase in controlling viral and B-cells genes expression, thus highlighting a novel interaction between the virus and the cellular epigenome.

microbiology↗