Epstein-Barr virus down-regulates tumor suppressor DOK1 expression

The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2′-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis.Fil: Siouda, Maha. World Health Organization; FranciaFil: Frecha, Cecilia Ariana. World Health Organization; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Accardi, Rosita. World Health Organization; FranciaFil: Yue, Jiping. World Health Organization; FranciaFil: Cuenin, Cyrille. World Health Organization; FranciaFil: Grufat, Henri. Inserm; Francia. Université Claude Bernard Lyon 1; Francia. Centre National de la Recherche Scientifique; Francia. Ecole Normale Supérieure; FranciaFil: Manet, Evelyne. Inserm; Francia. Université Claude Bernard Lyon 1; Francia. Centre National de la Recherche Scientifique; Francia. Ecole Normale Supérieure; FranciaFil: Herceg, Zdenko. World Health Organization; FranciaFil: Sylla, Bakary S.. World Health Organization; FranciaFil: Tommasino, Massimo. World Health Organization; Franci

Human mitochondrial DNA is extensively methylated in a non-CpG context

Mitochondrial dysfunction plays critical roles in cancer development and related therapeutic response; however, exact molecular mechanisms remain unclear. Recently, alongside the discovery of mitochondrial-specific DNA methyltransferases, global and site-specific methylation of the mitochondrial genome has been described. Investigation of any functional consequences however remains unclear and debated due to insufficient evidence of the quantitative degree and frequency of mitochondrial DNA (mtDNA) methylation. This study uses WGBS to provide the first quantitative report of mtDNA methylation at single base pair resolution. The data show that mitochondrial genomes are extensively methylated predominantly at non-CpG sites. Importantly, these methylation patterns display notable differences between normal and cancer cells. Furthermore, knockdown of DNA methyltransferase enzymes resulted in a marked global reduction of mtDNA methylation levels, indicating these enzymes may be associated with the establishment and/or maintenance of mtDNA methylation. DNMT3B knockdown cells displayed a comparatively pronounced global reduction in mtDNA methylation with concomitant increases in gene expression, suggesting a potential functional link between methylation and gene expression. Together these results demonstrate reproducible, non-random methylation patterns of mtDNA and challenge the notion that mtDNA is lowly methylated. This study discusses key differences in methodology that suggest future investigations must allow for techniques that assess both CpG and non-CpG methylation.Institut National du Cancer (INCa, France); European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework; Foundation ARC pour la Recherche sur le Cancer (France); Plan Cancer-Eva-Inserm research grant (to Z.H.); Postdoctoral Fellowship from International Agency for Research on Cancer (to V.P.), partially supported by the EC FP7 Marie Curie Actions -People -Co-funding of regional, national and international programmes (COFUND)'. Funding for open access charge: Institut National du Cancer (INCa, France); European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework; Foundation ARC pour la Recherche sur le Cancer (France); Plan Cancer-Eva-Inserm research grant (to Z.H.)

Protective Mechanisms of Polyphenol-Enriched Blueberry Preparation in Preventing Inflammation in the Skin against UVB-Induced Damage in an Animal Model

UVB significantly impacts the occurrence of cutaneous disorders, ranging from inflammatory to neoplastic diseases. Polyphenols derived from plants have been found to exhibit photoprotective effects against various factors that contribute to skin cancer. During the fermentation of the polyphenol-enriched blueberry preparation (PEBP), small oligomers of polyphenols were released, thus enhancing their photoprotective effects. This study aimed to investigate the protective effects of PEBP on UVB-induced skin inflammation. Topical preparations of polyphenols were applied to the skin of dorsally shaved mice. Mice were subsequently exposed to UVB and were sacrificed 90 min after UVB exposure. This study revealed that pretreatment with PEBP significantly inhibited UVB-induced recruitment of mast and neutrophil cells and prevented the loss of skin thickness. Furthermore, the findings show that PEBP treatment resulted in the downregulation of miR-210, 146a, and 155 and the upregulation of miR-200c and miR-205 compared to the UVB-irradiated mice. Additionally, PEBP was found to reduce the expression of IL-6, IL-1β, and TNFα, inhibiting COX-2 and increasing IL-10 after UVB exposure. Moreover, DNA methylation analysis indicated that PEBP might potentially reduce the activation of inflammation-related pathways such as MAPK, Wnt, Notch, and PI3K-AKT signaling. Our finding suggests that topical application of PEBP treatment may effectively prevent UVB-induced skin damage by inhibiting inflammation

Bariatric surgery-induced weight loss and associated genome-wide DNA-methylation alterations in obese individuals

Obesity is a multifactorial and chronic condition of growing universal concern. It has recently been reported that bariatric surgery is a more successful treatment for severe obesity than other noninvasive interventions, resulting in rapid significant weight loss and associated chronic disease remission. The identification of distinct epigenetic patterns in patients who are obese or have metabolic imbalances has suggested a potential role for epigenetic alterations in causal or mediating pathways in the development of obesity-related pathologies. Specific changes in the epigenome (DNA methylome), associated with metabolic disorders, can be detected in the blood. We investigated whether such epigenetic changes are reversible after weight loss using genome-wide DNA methylome analysis of blood samples from individuals with severe obesity (mean BMI ~ 45) undergoing bariatric surgery

Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation

Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. Theseinteractions takeplace in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.Institut National du Cancer (INCa, France, in part); European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework; Fondation ARC pour la Recherche sur le Cancer (France) (to Z.H.); Fonds National de la Recherche, Luxembourg [10100060 to A.S.]; IARC Fellowship (Marie Curie actions – People – COFUND to N.F.J., in part); PoSTDoctoral Fellowship of the Basque Government; Swiss National Science Foundation (SNSF) (to L.V., V.Y., R.M.). Funding for open access charge: IARC regular budge

Environmentally sensitive hotspots in the methylome of the early human embryo

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental 'hotspots' providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease

Upper aerodigestive tract squamous cell carcinomas show distinct overall DNA methylation profiles and different molecular mechanisms behind WNT signaling disruption

SIMPLE SUMMARY: Squamous cell carcinomas of the upper aerodigestive tract are highly incident, lethal, and share the same epithelial lining of origin, risk factors and genetic alterations. However, their biological and clinical behaviors differ, having an impact on patient survival. This study aimed at identifying the main DNA methylation differences between these tumors, giving an overview of the main genomic regions affected, whether DNA methylation gains or losses are more common, the impact on gene expression and the signaling pathways affected. This knowledge will help identifying potential site-specific biomarkers as well as shedding light on whether epigenetic mechanisms explain, at least in part, the diverse behavior of upper aerodigestive tract tumors. ABSTRACT: Upper aerodigestive tract (UADT) tumors present different biological behavior and prognosis, suggesting specific molecular mechanisms underlying their development. However, they are rarely considered as single entities (particularly head and neck subsites) and share the most common genetic alterations. Therefore, there is a need for a better understanding of the global DNA methylation differences among UADT tumors. We performed a genome-wide DNA methylation analysis of esophageal (ESCC), laryngeal (LSCC), oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas, and their non-tumor counterparts. The unsupervised analysis showed that non-tumor tissues present markedly distinct DNA methylation profiles, while tumors are highly heterogeneous. Hypomethylation was more frequent in LSCC and OPSCC, while ESCC and OSCC presented mostly hypermethylation, with the latter showing a CpG island overrepresentation. Differentially methylated regions affected genes in 127 signaling pathways, with only 3.1% of these being common among different tumor subsites, but with different genes affected. The WNT signaling pathway, known to be dysregulated in different epithelial tumors, is a frequent hit for DNA methylation and gene expression alterations in ESCC and OPSCC, but mostly for genetic alterations in LSCC and OSCC. UADT tumor subsites present differences in genome-wide methylation regarding their profile, intensity, genomic regions and signaling pathways affected

Detection of human papillomaviruses in paired healthy skin and actinic keratosis by next generation sequencing

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DNA methylation changes associated with risk factors in tumors of the upper aerodigestive tract

Cancers of the upper aerodigestive tract (UADT) are common forms of malignancy associated with tobacco and alcohol exposures, although human papillomavirus and nutritional deficiency are also important risk factors. While somatically acquired DNA methylation changes have been associated with UADT cancers, what triggers these events and precise epigenetic targets are poorly understood. In this study, we applied quantitative profiling of DNA methylation states in a panel of cancer-associated genes to a case-control study of UADT cancers. Our analyses revealed a high frequency of aberrant hypermethylation of several genes, including MYOD1, CHRNA3 and MTHFR in UADT tumors, whereas CDKN2A was moderately hypermethylated. Among differentially methylated genes, we identified a new gene (the nicotinic acetycholine receptor gene) as target of aberrant hypermethylation in UADT cancers, suggesting that epigenetic deregulation of nicotinic acetycholine receptors in non-neuronal tissues may promote the development of UADT cancers. Importantly, we found that sex and age is strongly associated with the methylation states, whereas tobacco smoking and alcohol intake may also influence the methylation levels in specific genes. This study identifies aberrant DNA methylation patterns in UADT cancers and suggests a potential mechanism by which environmental factors may deregulate key cellular genes involved in tumor suppression and contribute to UADT cancers.IARCIARCla Ligue National (Francaise) Contre le Cancerla Ligue National (Francaise) Contre le CancerNational Institutes of Health/National Cancer Institute (NIH/NCI), United StatesNational Institutes of Health/National Cancer Institute (NIH/NCI), United StatesAssociation pour la Recherche sur le Cancer (ARC, France)l'Association pour la Recherche sur le Cancer (ARC), Francela Ligue Nationale (Francaise) Contre le Cancer (Comite SaoneetLoire), Francela Ligue Nationale (Francaise) Contre le Cancer (Comite Saone-et-Loire), FranceSwiss Bridge AwardSwiss Bridge Awar

Los Montes Submarinos de la Plataforma Marginal de Motril, Mar de Alborán: Interacción con las Masas de Agua Profunda

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