Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subject

Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process

Molecular analysis of a multistep lung cancer model induced by chronic inflammation reveals epigenetic regulation of p16 and activation of the DNA damage response pathway

The molecular hallmarks of inflammation-mediated lung carcinogenesis have not been fully clarified, mainly due to the scarcity of appropriate animal models. We have used a silica-induced multistep lung carcinogenesis model driven by chronic inflammation to study the evolution of molecular markers and genetic alterations. We analyzed markers of DNA damage response (DDR), proliferative stress, and telomeric stress: gamma-H2AX, p16, p53, and TERT. Lung cancer-related epigenetic and genetic alterations, including promoter hypermethylation status of p16(CDKN2A), APC, CDH13, Rassf1, and Nore1A, as well as mutations of Tp53, epidermal growth factor receptor, K-ras, N-ras, and c-H-ras, have been also studied. Our results showed DDR pathway activation in preneoplastic lesions, in association with inducible nitric oxide synthase and p53 induction. p16 was also induced in early tumorigenic progression and was inactivated in bronchiolar dysplasias and tumors. Remarkably, lack of mutations of Ras and epidermal growth factor receptor, and a very low frequency of Tp53 mutations suggest that they are not required for tumorigenesis in this model. In contrast, epigenetic alterations in p16(CDKN2A), CDH13, and APC, but not in Rassf1 and Nore1A, were clearly observed. These data suggest the existence of a specific molecular signature of inflammation-driven lung carcinogenesis that shares some, but not all, of the molecular landmarks of chemically induced lung cancer

Predictive Value of Cardiac Magnetic Resonance Feature Tracking after Acute Myocardial Infarction: A Comparison with Dobutamine Stress Echocardiography

[EN] In acute ST-segment elevation myocardial infarction (STEMI) late gadolinium enhancement (LGE) may underestimate segmental functional recovery. We evaluated the predictive value of cardiac magnetic resonance (CMR) feature-tracking (FT) for functional recovery and whether it incremented the value of LGE compared to low-dose dobutamine stress echocardiography (LDDSE) and speckle-tracking echocardiography (STE). Eighty patients underwent LDDSE and CMR within 5-7 days after STEMI and segmental functional recovery was defined as improvement in wall-motion at 6-months CMR. Optimal conventional and FT parameters were analyzed and then also applied to an external validation cohort of 222 STEMI patients. Circumferential strain (CS) was the strongest CMR-FT predictor and addition to LGE increased the overall accuracy to 74% and was especially relevant in segments with 50-74% LGE (AUC 0.60 vs. 0.75, p = 0.001). LDDSE increased the overall accuracy to 71%, and in the 50-74% LGE subgroup improved the AUC from 0.60 to 0.69 (p = 0.039). LGE + CS showed similar value as LGE + LDDSE. In the validation cohort, CS was also the strongest CMR-FT predictor of recovery and addition of CS to LGE improved overall accuracy to 73% although this difference was not significant (AUC 0.69, p = 0.44). Conclusion: CS is the strongest CMR-FT predictor of segmental functional recovery after STEMI. Its incremental value to LGE is comparable to that of LDDSE whilst avoiding an inotropic stress agent. CS is especially relevant in segments with 50-74% LGE where accuracy is lower and further testing is frequently required to clarify the potential for recovery.This research was supported by the Instituto de Salud Carlos III and co-funded by Fondo Europeo de Desarrollo Regional (FEDER) (grant numbers PI17/01836 and CIBERCV16/11/00486). JG and DM acknowledge financial support from the "Agencia Valenciana de la Innovacion, Generalitat Valenciana" (grant) and from the "Conselleria d'Educacio, Investigacio, Cultura i Esport, Generalitat Valenciana" (grant number AEST/2019/037).Valente, FX.; Gavara-Doñate, J.; Gutiérrez, L.; Rios-Navarro, C.; Rello, P.; Maymi, M.; Fernandez-Galera, R.... (2021). Predictive Value of Cardiac Magnetic Resonance Feature Tracking after Acute Myocardial Infarction: A Comparison with Dobutamine Stress Echocardiography. Journal of Clinical Medicine. 10(22):1-12. https://doi.org/10.3390/jcm10225261S112102

S-adenosylmethionine Levels Regulate the Schwann Cell DNA Methylome

SummaryAxonal myelination is essential for rapid saltatory impulse conduction in the nervous system, and malformation or destruction of myelin sheaths leads to motor and sensory disabilities. DNA methylation is an essential epigenetic modification during mammalian development, yet its role in myelination remains obscure. Here, using high-resolution methylome maps, we show that DNA methylation could play a key gene regulatory role in peripheral nerve myelination and that S-adenosylmethionine (SAMe), the principal methyl donor in cytosine methylation, regulates the methylome dynamics during this process. Our studies also point to a possible role of SAMe in establishing the aberrant DNA methylation patterns in a mouse model of diabetic neuropathy, implicating SAMe in the pathogenesis of this disease. These critical observations establish a link between SAMe and DNA methylation status in a defined biological system, providing a mechanism that could direct methylation changes during cellular differentiation and in diverse pathological situations

Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes

Deletions of chromosome 8p are a recurrent event in B-cell non-Hodgkin lymphoma (B-NHL), suggesting the presence of a tumor suppressor gene. We have characterized these deletions using comparative genomic hybridization to microarrays, fluorescence in situ hybridization (FISH) mapping, DNA sequencing, and functional studies. A minimal deleted region (MDR) of 600 kb was defined in chromosome 8p21.3, with one mantle cell lymphoma cell line (Z138) exhibiting monoallelic deletion of 650 kb. The MDR extended from bacterial artificial chromosome (BAC) clones RP11-382J24 and RP11-109B10 and included the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor gene loci. Sequence analysis of the individual expressed genes within the MDR and DNA sequencing of the entire MDR in Z138 did not reveal any mutation. Gene expression analysis and quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) showed down-regulation of TRAIL-R1 and TRAIL-R2 receptor genes as a consistent event in B-NHL with 8p21.3 loss. Epigenetic inactivation was excluded via promoter methylation analysis. In vitro studies showed that TRAIL-induced apoptosis was dependent on TRAIL-R1 and/or -R2 dosage in most tumors. Resistance to apoptosis of cell lines with 8p21.3 deletion was reversed by restoration of TRAIL-R1 or TRAIL-R2 expression by gene transfection. Our data suggest that TRAIL-R1 and TRAIL-R2 act as dosage-dependent tumor suppressor genes whose monoallelic deletion can impair TRAIL-induced apoptosis in B-cell lymphoma

DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia

Background: Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required. Methodology/Principal Findings: We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/ progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients. Conclusions/Significance: Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signatur

Guía de antídotos para los centros hospitalarios de Cataluña

Intoxicació aguda; Emergències toxicològiques; Serveis d'urgènciesAcute poisoning; Toxicological emergencies; Emergency serviceIntoxicación aguda; Emergencias toxicológicas; Servicios de urgenciasL’elaboració de la Guia d’antídots parteix de la necessitat d’establir de forma coordinada la disponibilitat qualitativa i quantitativa d’antídots que han de tenir els diferents àmbits sanitaris de Catalunya. Aquesta guia té la finalitat d’unificar els criteris de selecció i d’utilització dels fàrmacs adients per als tractaments d’emergències toxicològiques en qualsevol Servei d’Urgència dels centres hospitalaris de Catalunya.This document is drafted according to the need to arrange a coordinated manner of qualitative and quantitative availability of antidotes that should have different health areas in Catalonia. This guide aims to unify criteria and appropriate use of drugs for the treatment of any toxicological emergencies in any emergency medical services in Catalonian hospitals.La elaboración de la Guía de antídotos parte de la necesidad de establecer de forma coordinada la disponibilidad cualitativa y cuantitativa de antídotos que deben tener los diferentes ámbitos sanitarios de Cataluña. Esta guía tiene la finalidad de unificar los criterios de selección y de utilización de los fármacos adecuados para los tratamientos de emergencias toxicológicas en los Servicios de Urgencia de los centros hospitalarios de Cataluña

Determinacions del perfil genètic de tumors sòlids de l’adult

Perfil genètic; Tumors sòlids; Adults; PrecisióPerfil genético; Tumores sólidos; Adultos; PrecisiónGenetic profile; Solid tumors; Adults; AccuracyEn aquest estudi s’ha definit la llista de gens per a cada patologia i tots ells han estat seleccionats atenent a; la seva utilitat diagnòstica per definir els subtipus tumorals en localitzacions tumorals molt concretes; la seva utilitat pronòstica i predictiva, sempre que això comporti un canvi d’actitud terapèutica; la seva utilitat terapèutica per a la indicació de l’ús de fàrmacs diana

Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR

Metastasis is respoMetastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors