Biology subjects

Romero, M.

Publications and source records attributed to Romero, M..

15 recordsLinked to original sources

bioRxiv2026

Z-AAT impairs organelle homeostasis and reduces adaptive response to lipids in alpha-1 antitrypsin deficiency models

Alpha-1 antitrypsin deficiency (AATD) caused by the Z variant leads to hepatic accumulation of misfolded AAT polymers and liver disease. Although proteotoxic stress is well established, its impact on lipid metabolism, mitochondrial function, and organelle homeostasis remains incompletely understood. The effects of Z-AAT accumulation were investigated in Z-HepG2 cells and 3D patient-derived ZZ hepatic organoids through protein aggregation, lipid storage, mitochondrial structure and function, peroxisomal dynamics, and comprehensive transcriptomic and proteomic analyses. Z-AAT expression led to intracellular polymer accumulation and reduced secretion, together with lipid accumulation, mitochondrial structural abnormalities, increased mitochondrial number but impaired respiratory capacity. Metabolic profiling revealed reduced oxidative phosphorylation and partial reliance on glucose metabolism. Peroxisomes displayed increased mass, consistent with altered lipid handling. Multi-omics analysis demonstrated widespread transcriptional and proteomic reprogramming related to protein synthesis, lipid metabolism, and mitochondrial function. Proteomic analysis confirmed proteotoxic stress-induced mitochondrial dysfunction, impaired lipid handling, and activation of stress response, inflammatory and vesicular trafficking pathways. Importantly, lipid supplementation elicited adaptive mitochondrial transcriptional responses in control cells, whereas Z-HepG2 cells showed a blunted response to lipid challenge. In conclusion, Z-AAT accumulation disrupts hepatic lipid processing and impaired mitochondrial and peroxisomal homeostasis, producing diminished metabolic flexibility likely contributing to AATD-associated liver disease.

molecular biology↗

bioRxiv2026

SdiA as a Repressor of Phagocytosis and Intracellular Survival in Klebsiella pneumoniae: Insights from Macrophage and Amoeba Models

1.In 2024, the World Health Organisation (WHO) classified Klebsiella pneumoniae as a maximum priority pathogen for the development of new alternatives to antibiotics. In this context, understanding the regulation of key virulence mechanisms is essential. Here, we investigated the role of the orphan quorum-sensing receptor SdiA in modulating virulence-associated processes during macrophage infection. Deletion of sdiA ({Delta}sdiA) significantly increased susceptibility to phagocytosis, as demonstrated using an amoeba predation model in which mutant strains formed larger clearance zones compared to wild-type bacteria. This phenotype was also observed in murine macrophages, where {Delta}sdiA strains exhibited increased adhesion (1.5 to 2.5-fold) and phagocytic uptake. Reduced uronic acid levels were also quantified in mutant strains, indirectly indicating a diminished capsule production, likely contributing to this enhanced phagocytosis. Despite enhanced uptake, {Delta}sdiA strains showed increased intracellular survival and replication rates within macrophages, leading to reduced host cell viability. This effect occurred despite loss of interbacterial killing capacity against E. coli, suggesting that enhanced intracellular fitness is not driven by classical antibacterial offensive mechanisms. Notably, mutant-infected macrophages displayed increased generation of reactive oxygen species (ROS), NF-{kappa}B expression, and pro-inflammatory cytokines (mCXCL10 and mTNF) production, indicating that macrophage defence mechanisms are not impaired during mutant infection. Overall, bacterial survival of {Delta}sdiA could result from overwhelming, rather than actively suppressing, host defences. Together, these findings identify SdiA as a negative regulator of phagocytosis and intracellular survival in K. pneumoniae and highlight a context-dependent role in virulence. This work provides new insights into the regulatory networks governing host-pathogen interactions and bacterial adaptation to the intracellular environment. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/725935v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1d45bfdorg.highwire.dtl.DTLVardef@e3547forg.highwire.dtl.DTLVardef@c078f9org.highwire.dtl.DTLVardef@46408a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Loss of sdiA strongly affects phagocytosis, as mutant strains showed increasing adhesion (1.5 to 2.5-fold) and phagocytic uptake. Diminished capsule production could be contributing to this enhanced phagocytosis, as reduced uronic acid levels were also quantified in mutant strains. Despite being internalized at higher rates, mutants exhibited enhanced intracellular survival and replication, reducing macrophage viability. This fitness advantage occurred independently of classical offensive mechanisms, as evidenced by a lost ability to kill E. coli. Notably, mutant-infected macrophages mounted a stronger immune response, marked by elevated ROS, NF-{kappa}B expression, and pro-inflammatory cytokines production (mCXCL10 and mTNF). Together, these findings suggest that strains survive by overwhelming, rather than suppressing, host immune defences. Created with Biorender (https://www.biorender.com/). C_FIG HighlightsO_LISdiA deletion in K. pneumoniae increases susceptibility to phagocytosis. C_LIO_LIThe mutant strains exhibit reduced uronic acid levels, indicative of capsule production. C_LIO_LISdiA mutants show enhanced intracellular survival and higher macrophage death. C_LIO_LIMutant infected macrophages have higher NF-{kappa}B, TNF, and CXCL10 responses. C_LIO_LISdiA-deficient strains lose predatory capacity against E. coli. C_LI

microbiology↗

bioRxiv2025

Effects of Combination Therapy of a CDK4/6 and MEK Inhibitor in Diffuse Midline Glioma Preclinical Models

BackgroundDiffuse midline glioma (DMG) is an incurable brain cancer without a single FDA-approved drug that prolongs survival. CDK4/6 inhibitors have been evaluated in children with DMG with limited efficacy. Since MAPK pathway activation is upstream of cell proliferation, we hypothesized that MEK inhibitors may increase the anti-tumor effects of CDK4/6 inhibitors. Here, we evaluated the efficacy of the CDK4/6 inhibitor ribociclib and the MEK inhibitor trametinib in human and murine DMG models to investigate combinational effects. MethodsWe conducted in vitro and in vivo assays using DMG cell lines from human patient-derived xenografts (PDX) and murine genetically engineered models (GEM). In vitro, we assessed synergy across human DMG lines. In vivo, we evaluated therapeutic effects with histological examinations, survival analysis, pharmacokinetic measurements, and RNA-sequencing analysis. ResultsIn vitro, ribociclib and trametinib had variable synergistic effects against human DMG cell lines. In vivo, a five-day treatment with combination therapy in the GEM DMG model significantly decreased cell proliferation and increased apoptosis compared with the vehicle, with trametinib having mostly cytotoxic effects and ribociclib having primarily cytostatic effects. In addition, a 21-day treatment with combination therapy significantly prolonged mice survival compared with the vehicle in the GEM DMG model (median survival: 112 days vs. 71.5 days, log rank test p=0.0195). In an orthotopic PDX model, combination therapy did not prolong mice survival compared with vehicle, ribociclib, and trametinib. LC/MS analysis showed adequate drug delivery across the blood-brain-barrier (BBB) into tumor tissue in both GEM and PDX models. Transcriptomic analysis in the GEM model suggests that combination therapy inhibited the MAPK pathway and inflammation. ConclusionsCombination therapy with ribociclib and trametinib significantly prolonged survival in the GEM model but not in the PDX model, highlighting the importance of testing novel therapies in diverse models. Key PointsO_LICombination therapy had cytotoxic and cytostatic effects in vivo in the GEM model. C_LIO_LICombination therapy had variable synergy in vitro in human DIPG models. C_LIO_LICombination therapy significantly prolonged mice survival compared with the vehicle in the GEM model. C_LIO_LICombination therapy did not prolong survival in the PDX model. C_LIO_LITranscriptional analysis suggests that the combination modulated inflammation in the GEM model. C_LIO_LIThis work highlights the importance of testing novel therapies in diverse models. C_LI Importance of the StudyDMG is an incurable brain cancer without a single FDA-approved drug that prolongs survival. CDK4/6 inhibitors have been evaluated in children with DMG with limited efficacy. As MAPK pathway activation is known to be upstream of cell proliferation, we hypothesize that combination therapy will have additive effects relative to monotherapy. In this study, we evaluated the efficacy of the CDK4/6 inhibitor ribociclib and the MEK inhibitor trametinib in GEM and PDX DMG models. In vitro, the inhibitor combination demonstrated variable synergy in DMG human cell-lines, but in vivo, it had limited efficacy in a PDX orthotopic model. In the GEM model, the combination prolonged survival compared with the vehicle and with single agents. PK studies showed similar drug levels in tumor tissue between the GEM and PDX models. Transcriptomic analysis in the GEM suggests that the drug combination significantly inhibited inflammation. These results highlight the importance of testing therapies in diverse models and suggest that this combination may be an effective therapy in patients with DMG.

cancer biology↗

bioRxiv2025

SIRT7 links H3K36ac epigenetic regulation with genome maintenance in the aging mouse testis

ABSTRACT/SUMMARYReproductive aging is an increasing health concern affecting family planning and overall well-being. While extensively studied in females, the mechanisms driving male reproductive aging remain largely unexamined. Here we found that mammalian Sirtuin 7 (SIRT7) sustains spermatogenesis in an age-dependent manner through the control of histone 3 lysine 36 acetylation (H3K36ac). SIRT7 deficiency in mice resulted in increased levels of H3K36ac in spermatogonia and spermatocytes. In a germ cell line, SIRT7 deficiency disrupted nucleosome stability and increased vulnerability to genotoxic stress. Importantly, undifferentiated spermatogonia, which are required for continuous sperm production, decreased prematurely in Sirt7-/- mice and showed genome damage accumulation. These changes were concurrent with age-dependent defects in homologous chromosome synapsis and partial meiotic arrest. Taken together, our results indicate that SIRT7 connects H3K36ac epigenetic regulation to long-term genome stability in male germ cells, ensuring steady-state spermatogenesis during the lengthy male reproductive lifespan.

cell biology↗

bioRxiv2024

Regulatory effects on virulence and phage susceptibility revealed by sdiA mutation in Klebsiella pneumoniae

The World Health Organization has identified multi-drug resistant (MDR) Klebsiella pneumoniae strains as the highest priority in 2024. SdiA, a LuxR-like quorum sensing (QS) receptor that responds to N-acyl-homoserine lactones (AHLs), exerts a substantial regulatory influence on the virulence of numerous Gram-negative bacteria. The function of this receptor in the virulence of K. pneumoniae remains uncertain. Nevertheless, further investigation into the significance of this receptor is needed, as it represents an intriguing avenue with the potential to contribute to the development of novel antimicrobial strategies. The objective of the present study was to elucidate the function of SdiA in K. pneumoniae biofilm formation and virulence. To this end, a genetic knockout of sdiA was conducted, and virulence-related phenotypic studies were performed following AHL provision. The results demonstrate that SdiA deficiency increases susceptibility to phage infection and human serum resistance, and promotes biofilm maturation and cell filamentation. No effect on virulence was observed in vivo in the Galleria mellonella infection model. The addition of N-hexanoyl-L-homoserine lactone (C6-HSL) promoted SdiA-dependent biofilm maturation but also enhanced serum resistance and reduced virulence against G. mellonella in the absence of SdiA. The results of this study demonstrate that C6-HSL and SdiA exert a dual influence on virulence phenotypes, operating both independently and hierarchically. These findings provide new insights into the virulence of K. pneumoniae and its regulation by SdiA. ImportanceThis study represents a significant contribution to our understanding of the complex regulatory mechanisms that govern the virulence of multi-drug resistant Klebsiella pneumoniae through quorum sensing (QS). The study offers insights into the function of SdiA, a QS receptor, in the regulation of biofilm formation, susceptibility to phage infection, serum resistance, and cell filamentation in this bacterium. Furthermore, the findings of this study demonstrate that exogenous N-acyl-homoserine lactone (AHL) signalling influences the aforementioned virulence phenotypes in both a SdiA-dependent and independent manner, as well as in a hierarchical manner.

microbiology↗

bioRxiv2024

Two retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity

The human genome contains 24 gag-like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag-like genes PNMA1 and PNMA4 support reproductive capacity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. Analysis of donated human ovaries shows that expression of both genes declines normally with aging, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

genetics↗

bioRxiv2024

Multiple intersecting pathways are involved in the phosphorylation of CPEB1 to activate translation during mouse oocyte meiosis

The RNA-binding protein cytoplasmic polyadenylation element binding 1 (CPEB1) plays a fundamental role in the regulation of mRNA translation in oocytes. However, the nature of protein kinase cascades modulating the activity of CPEB1 is still a matter of controversy. Using genetic and pharmacological tools and detailed time courses, here we have reevaluated the relationship between CPEB1 phosphorylation and the activation of translation during mouse oocyte maturation. We show that both the CDK1/MAPK and AURKA/PLK1 pathways converge on the phosphorylation of CPEB1 during prometaphase. Only inactivation of the CDK1/MAPK pathway disrupts translation, while inactivation of either pathway leads to CPEB1 stabilization. However, stabilization of CPEB1 induced by inactivation of the AURKA/PLK1 does not affect translation, indicating that destabilization/degradation can be dissociated from translational activation. The accumulation of the endogenous CCNB1 protein closely recapitulates the translation data. These findings support the overarching hypothesis that the activation of translation in prometaphase in mouse oocytes relies on a CDK1-dependent CPEB1 phosphorylation, and this translational activation precedes CPEB1 destabilization.

developmental biology↗

bioRxiv2020

Topographical biomaterials instruct bacterial surface attachment and the in vivo host-pathogen response

Bio-instructive materials that prevent bacterial biofilm formation and drive an appropriate host immune response have the potential to significantly reduce the burden of medical device-associated infections. Since bacterial surface attachment is known to be sensitive to surface topography, we experimentally survey 2,176 combinatorially generated shapes using an unbiased high-throughput micro topographical screen on polystyrene. This identifies topographies that reduce colonization in vitro by up to 15-fold compared with a flat surface for both motile and non-motile bacterial pathogens. Equivalent reductions are achieved on polyurethane, a polymer commonly used in medical devices. Using machine learning methods, a set of design rules based on generalisable descriptors is established for predicting bacteria-resistant micro topographies. In a murine foreign body infection model, anti-attachment topographies are shown to be refractory to P. aeruginosa and to recruit a productive host response, highlighting the potential of simple topographical patterning of non-eluting implants for preventing medical device associated infections.

microbiology↗

bioRxiv2020

Stage-specific muscle wasting mechanisms in a novel cancer cachexia mouse model for ovarian granulosa cell tumor

Cachexia is a progressive muscle wasting syndrome that increases mortality risk in cancer patients, while there are still no effective treatment due to the complexity of syndrome and the lack of preclinical models. We identified a transgenic mice model with ovarian granulosa cell tumors mimic the progression of cachexia seen in humans, including drastic weight loss, skeletal muscle wasting and increased serum cachexia biomarker activin A and GDF15. Hypercatabolism was detected in skeletal muscle, having upregulation of E3 ligases Atrogin-1 and Murf-1. Our cachexia model exhibited stage-specific muscle wasting mechanisms. At precachexia stage, elevation of activin A activates p38 MAPK. Inhibition of activin A with Follistatin reversed weight loss at precachexia stage. At cachexia stage, energy stress in skeletal muscle activates AMPK and leads to upregulation of FoxO3. Our results indicate this novel preclinical cancer cachexia model is exploitable for studying pathophysiological mechanisms and testing therapeutic agents of cachexia.

cancer biology↗

bioRxiv2020

Expanding Biomaterial Surface Topographical Design Space through Natural Surface Reproduction

Surface topography guides cell behavior and is a tool to endow biomaterials with bioactive properties. The large number of possible designs makes it challenging to find the optimal surface structure to induce a specific cell response. The TopoChip platform is currently the largest collection of topographies with 2176 in silico designed micro-topographies. Still, it is exploring only a small part of the design space due to the boundary conditions of the design algorithm and the surface engineering strategy. Inspired by the diversity of natural surfaces, we assessed to what extend we could expand the topographical design space and consequently the resulting cellular responses using natural surfaces. To this end, we replicated twenty-six plant and insect surfaces in polystyrene and quantified their surface properties using white light interferometry, image analysis and principle component analysis. Next, we quantified mesenchymal stem cell morphology and the pattern of Pseudomonas aeruginosa colonization and compared it to previous data from TopoChip screens. Our data show that natural surfaces extended the TopoChip design space. Moreover, the natural surfaces induced MSC morphologies and bacterial attachment patterns not previously observed on the TopoChip. In the future, we will train our design algorithms with the results obtained by natural surface imprint experiments to further explore the design space and bio-active properties of surface topography.

cell biology↗

bioRxiv2019

Rhizosphere metagenomics of mine tailings colonizing plants: assembling and selecting synthetic bacterial communities to enhance in situ bioremediation

Mine tailings phytostabilization has been proposed as a bioremediation strategy to constrain the contaminants dispersion using plants to limit the effects of erosion. Rhizospheric bacteria impact plant health and facilitate plant establishment through their metabolic functions, which could be relevant in bioremediation strategies. We studied both culturable and metagenomic diversity or rhizospheric bacteria of mine tailings colonizing plants of an abandoned mine operation in Nacozari de Garcia, Sonora, Mexico. Diversity was described through amplification of the 16S rRNA gene and whole metagenome shotgun sequencing of both environmental and cultured rhizosphere associated microbes. The culturable bacteria were assembled in a synthetic community (SC; 235 bacteria genera). Subsequently, we performed an experimental evolution setup with the SC, selecting for heavy metal resistance, microbial competition, and the ability for growing in plant-derived nutrient sources. The selection experiment show that bacteria diversity decreases from the environmental culture-free microbiomes to the mine tailings rhizospheres and the experimental evolution outcome: the synthetic community (FSC; 43 bacteria genera). The rhizosphere communities shifted from the dominance of Actinobacteria in their environment to Proteobacteria in the cultivated consortia and the synthetic communities. Both environmental and cultured metagenomes contained plant-growth promotion, heavy-metal homeostasis, and antibiotic resistance predicted genes. The FSC included predicted proteins related to plant-growth promotion such as siderophore production and plant hormone regulation proteins. We reconstructed a metagenome assembled genomic sequence named Enterobacter sp., Nacozari. The recovered Enterobacter sp. Nacozari, have predicted coding genes for direct and indirect plant growth promotion along with adhesion and oxidative stress-related proteins. The metabolic potential of the FSC presents promising features that might make it useful for plant-growth promotion in tailored phytostabilization strategies for the abandoned mine-tailings of Nacozari.

genomics↗

bioRxiv2019

Arbovirus emergence in temperate climates: the case of Cordoba, Argentina, 2009-2018

The distribution of arbovirus disease transmission is expanding from the tropics and subtropics into temperate regions worldwide. The aim of this study was to characterize the emergence of arboviruses in the temperate city of Cordoba, Argentina (2009-2018), including dengue virus (DENV) serotypes and origins of imported cases. The first cases of dengue fever were reported in 2009, followed by outbreaks in 2013, 2015, and 2016, each outbreak having greater incidence than the previous. DENV1 was the predominant serotype. Cases were imported from Venezuela, Brazil, Bolivia, Mexico, Costa Rica, and northern Argentina. The first imported cases of chikungunya were reported in 2014 and the first imported and autochthonous of Zika fever in 2016. Regional efforts are needed to strengthen surveillance, due to the key role of human movement in arbovirus introductions.

epidemiology↗

bioRxiv2019

Muscle fiber hypertrophy in response to 6 weeks of high-volume resistance training in trained young men is largely attributed to sarcoplasmic hypertrophy

Cellular adaptations that occur during skeletal muscle hypertrophy in response to high-volume resistance training are not well-characterized. Therefore, we sought to explore how actin, myosin, sarcoplasmic protein, mitochondrial, and glycogen concentrations were altered in individuals that exhibited mean skeletal muscle fiber cross-sectional area (fCSA) hypertrophy following 6 weeks of high-volume resistance training. Thirty-one previously resistance-trained, college-aged males (mean {+/-} standard deviation: 21{+/-}2 years, 5{+/-}3 training years) had vastus lateralis (VL) muscle biopsies obtained prior to training (PRE), at week 3 (W3), and at week 6 (W6). Muscle tissue from 15 subjects exhibiting PRE to W6 VL mean fCSA increases ranging from 320-1600 m2 was further interrogated using various biochemical and histological assays as well as proteomic analysis. Seven of these individuals donated a VL biopsy after refraining from training 8 days following the last training session (W7) to determine how deloading affected biomarkers. The 15 fCSA hypertrophic responders experienced a +23% increase in mean fCSA from PRE to W6 (p<0.001) and, while muscle glycogen concentrations remained unaltered, citrate synthase activity levels decreased by 24% (p<0.001) suggesting mitochondrial volume decreased. Interestingly, both myosin and actin concentrations decreased ~30% from PRE to W6 (p<0.05). Phalloidin-actin staining similarly revealed actin concentrations per fiber decreased from PRE to W6. Proteomic analysis of the sarcoplasmic fraction from PRE to W6 indicated 40 proteins were up-regulated (p<0.05), KEGG analysis indicated that the glycolysis/gluconeogenesis pathway was upregulated (FDR sig. <0.001), and DAVID indicated that the following functionally-annotated pathways were upregulated (FDR value <0.05): a) glycolysis (8 proteins), b) acetylation (23 proteins), c) gluconeogenesis (5 proteins) and d) cytoplasm (20 proteins). At W7, sarcoplasmic protein concentrations remained higher than PRE (+66%, p<0.05), and both actin and myosin concentrations remained lower than PRE (~-50%, p<0.05). These data suggest that short-term high-volume resistance training may: a) reduce muscle fiber actin and myosin protein concentrations in spite of increasing fCSA, and b) promote sarcoplasmic expansion coincident with a coordinated up-regulation of sarcoplasmic proteins involved in glycolysis and other metabolic processes related to ATP generation. Interestingly, these effects seem to persist up to 8 days following training.

molecular biology↗

bioRxiv2019

Co-developing climate services for public health: stakeholder needs and perceptions for the prevention and control of Aedes-transmitted diseases in the Caribbean.

BackgroundSmall island developing states (SIDS) in the Caribbean region are challenged with managing the health outcomes of a changing climate. Health and climate sectors have partnered to co-develop climate services to improve the management of these diseases, for example, through the development of climate-driven early warning systems. The objective of this study was to identify health and climate stakeholder perceptions and needs in the Caribbean, with respect to the development of climate services for arboviruses (e.g. dengue, chikungunya, and Zika).\n\nMethodsStakeholders included public decision makers and practitioners from the climate and health sectors at the regional (Caribbean) level and from the countries of Dominica and Barbados. From April to June 2017, we conducted interviews (n=41), surveys (n=32), and national workshops with stakeholders. Survey responses were tabulated and audio recordings were transcribed and analyzed using qualitative coding to identify responses by research topic, country/region, and sector.\n\nResultsHealth practitioners indicated that their jurisdiction is currently experiencing an increased risk of diseases transmitted by Ae. aegypti due to climate variability, and most anticipated that this risk will increase in the future. National health sectors reported financial limitations and a lack of technical expertise in geographic information systems (GIS), statistics, and modeling, which constrained their ability to implement climate services for arboviruses. National climate sectors were constrained by a lack of personnel. Stakeholders highlighted the need to strengthen partnerships with the private sector, academia, and civil society. They identified a gap in local research on climate-arbovirus linkages, which constrained the ability of the health sector to make informed decisions. Strategies to strengthen the climate-health partnership included a top-down approach by engaging senior leadership, multi-lateral collaboration agreements, national committees on climate and health, and shared spaces of dialogue. Mechanisms for mainstreaming climate services for health operations to control arboviruses included climate-health bulletins and an online GIS platform that would allow for regional data sharing and the generation of spatiotemporal epidemic forecasts.\n\nConclusionsThese findings support the creation of interdisciplinary and intersectoral communities of practices and the co-design of climate services for the Caribbean public health sector. By fostering the effective use of climate information within health policy, research and practice, nations will have greater capacity to adapt to a changing climate.

scientific communication and education↗

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↗